The Cotney Lab

@article{Stewart:2019ke,
author = {Stewart, Thomas A and Liang, Cong and Cotney, Justin L and Noonan, James P and Sanger, Thomas J and Wagner, G{\"u}nter P},
title = {{Evidence against tetrapod-wide digit identities and for a limited frame shift in bird wings.}},
journal = {Nature Communications},
year = {2019},
volume = {10},
number = {1},
pages = {3244--13},
month = jul,
publisher = {Nature Publishing Group},
affiliation = {Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, 06520, USA. tomstewart@uchicago.edu.},
doi = {10.1038/s41467-019-11215-8},
pmid = {31324809},
pmcid = {PMC6642197},
language = {English},
rating = {0},
date-added = {2019-12-23T18:08:28GMT},
date-modified = {2019-12-23T18:09:38GMT},
abstract = {In crown group tetrapods, individual digits are homologized in relation to a pentadactyl ground plan. However, testing hypotheses of digit homology is challenging because it is unclear whether digits represent distinct and conserved gene regulatory states. Here we show dramatic evolutionary dynamism in the gene expression profiles of digits, challenging the notion that five digits have conserved developmental identities across amniotes. Transcriptomics shows diversity in the patterns of gene expression differentiation of digits, although the anterior-most digit of the pentadactyl limb has a unique, conserved expression profile. Further, we identify a core set of transcription factors that are differentially expressed among the digits of amniote limbs; their spatial expression domains, however, vary between species. In light of these results, we reevaluate the frame shift hypothesis of avian wing evolution and conclude only the identity of the anterior-most digit has shifted position, suggesting a 1,3,4 digit identity in the bird wing.},
url = {http://www.nature.com/articles/s41467-019-11215-8},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/FC/FC749320-9640-4593-B482-52A2031BE3E8.pdf},
file = {{FC749320-9640-4593-B482-52A2031BE3E8.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/FC/FC749320-9640-4593-B482-52A2031BE3E8.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1038/s41467-019-11215-8}}
}

@article{Hsiao:2019im,
author = {Hsiao, Jack S and Germain, Noelle D and Wilderman, Andrea and Stoddard, Christopher and Wojenski, Luke A and Villafano, Geno J and Core, Leighton and Cotney, Justin and Chamberlain, Stormy J},
title = {{A bipartite boundary element restricts UBE3A imprinting to mature neurons.}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2019},
volume = {116},
number = {6},
pages = {2181--2186},
month = feb,
affiliation = {Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403.},
doi = {10.1073/pnas.1815279116},
pmid = {30674673},
pmcid = {PMC6369781},
language = {English},
read = {Yes},
rating = {0},
date-added = {2019-03-20T20:57:28GMT},
date-modified = {2019-07-03T17:41:07GMT},
abstract = {Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is restricted to neurons by expression of UBE3A antisense transcript (UBE3A-ATS) from the paternally inherited allele, which silences the paternal allele of UBE3A in cis However, the mechanism restricting UBE3A-ATS expression and UBE3A imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of UBE3A-ATS in humans. Removal of this element led to up-regulation of UBE3A-ATS without repressing paternal UBE3A However, increasing expression of UBE3A-ATS in the absence of the boundary element resulted in full repression of paternal UBE3A, demonstrating that UBE3A imprinting requires both the loss of function from the boundary element as well as the up-regulation of UBE3A-ATS These results suggest that manipulation of the competition between UBE3A-ATS and UBE3A may provide a potential therapeutic approach for AS.},
url = {http://www.pnas.org/lookup/doi/10.1073/pnas.1815279116},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/46/460AFB66-72A1-47F6-A0E8-9DB8E821BBFD.pdf},
file = {{460AFB66-72A1-47F6-A0E8-9DB8E821BBFD.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/46/460AFB66-72A1-47F6-A0E8-9DB8E821BBFD.pdf:application/pdf;460AFB66-72A1-47F6-A0E8-9DB8E821BBFD.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/46/460AFB66-72A1-47F6-A0E8-9DB8E821BBFD.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1073/pnas.1815279116}}
}

@article{Blankvoort:2018fr,
author = {Blankvoort, Stefan and Witter, Menno P and Noonan, James and Cotney, Justin and Kentros, Cliff},
title = {{Marked Diversity of Unique Cortical Enhancers Enables Neuron-Specific Tools by Enhancer-Driven Gene Expression.}},
journal = {Current biology : CB},
year = {2018},
volume = {28},
number = {13},
pages = {2103--2114.e5},
month = jul,
affiliation = {Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU, Trondheim, Norway.},
doi = {10.1016/j.cub.2018.05.015},
pmid = {30008330},
language = {English},
read = {Yes},
rating = {0},
date-added = {2019-01-11T20:32:31GMT},
date-modified = {2019-03-29T19:57:46GMT},
abstract = {Understanding neural circuit function requires individually addressing their component parts: specific neuronal cell types. However, not only do the precise genetic mechanisms specifying neuronal cell types remain obscure, access to these neuronal cell types by transgenic techniques also remains elusive. Whereas most genes are expressed in the brain, the vast majority are expressed in many different kinds of neurons, suggesting that promoters alone are not sufficiently specific to distinguish cell types. However, there are orders of magnitude more distal genetic cis-regulatory elements controlling transcription (i.e., enhancers), so we screened for enhancer activity in microdissected samples of mouse cortical subregions. This identified thousands of novel putative enhancers, many unique to particular cortical subregions. Pronuclear injection of expression constructs containing such region-specific enhancers resulted in transgenic lines driving expression in distinct sets of cells specifically in the targeted cortical subregions, even though the parent gene's promoter was relatively non-specific. These data showcase the promise of utilizing the genetic mechanisms underlying the specification of diverse neuronal cell types for the development of genetic tools potentially capable of targeting any neuronal circuit of interest, an approach we call enhancer-driven gene expression (EDGE).},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0960982218306171},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/2C/2CDFA050-54CC-4638-9A9E-E293C1DD2F64.pdf},
file = {{2CDFA050-54CC-4638-9A9E-E293C1DD2F64.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/2C/2CDFA050-54CC-4638-9A9E-E293C1DD2F64.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1016/j.cub.2018.05.015}}
}

@article{Wilderman:2018kg,
author = {Wilderman, Andrea and VanOudenhove, Jennifer and Kron, Jeffrey and Noonan, James P and Cotney, Justin},
title = {{High-Resolution Epigenomic Atlas of Human Embryonic Craniofacial Development.}},
journal = {Cell reports},
year = {2018},
volume = {23},
number = {5},
pages = {1581--1597},
month = may,
affiliation = {Graduate Program in Genetics and Developmental Biology, UConn Health, Farmington, CT 06030, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA.},
doi = {10.1016/j.celrep.2018.03.129},
pmid = {29719267},
pmcid = {PMC5965702},
language = {English},
rating = {0},
date-added = {2019-01-11T20:31:54GMT},
date-modified = {2019-02-22T18:35:41GMT},
abstract = {Defects in patterning during human embryonic development frequently result in craniofacial abnormalities. The gene regulatory programs that build the craniofacial complex are likely controlled by information located between genes and within intronic sequences. However, systematic identification of regulatory sequences important for forming the human face has not been performed. Here, we describe comprehensive epigenomic annotations from human embryonic craniofacial tissues and systematic comparisons with multiple tissues and cell types. We identified thousands of tissue-specific craniofacial regulatory sequences and likely causal regions for rare craniofacial abnormalities. We demonstrate significant enrichment of common variants associated with orofacial clefting in enhancers active early~in embryonic development, while those associated with normal facial variation are enriched near the end of the embryonic period. These data are provided in easily accessible formats for both craniofacial researchers and clinicians to aid future experimental design and interpretation of noncoding~variation in those affected by craniofacial abnormalities.},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124718305175},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/E4/E4C0EE47-58C7-42BC-ACC9-3ECB451FCBD4.pdf},
file = {{E4C0EE47-58C7-42BC-ACC9-3ECB451FCBD4.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/E4/E4C0EE47-58C7-42BC-ACC9-3ECB451FCBD4.pdf:application/pdf;E4C0EE47-58C7-42BC-ACC9-3ECB451FCBD4.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/E4/E4C0EE47-58C7-42BC-ACC9-3ECB451FCBD4.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1016/j.celrep.2018.03.129}}
}

@article{Kalsner:2017kt,
author = {Kalsner, Louisa and Twachtman-Bassett, Jennifer and Tokarski, Kristin and Stanley, Christine and Dumont-Mathieu, Thyde and Cotney, Justin and Chamberlain, Stormy},
title = {{Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications.}},
journal = {Molecular Genetics {\&} Genomic Medicine},
year = {2017},
volume = {82},
number = {1},
pages = {150--185},
month = dec,
affiliation = {Connecticut Children's Medical Center, Farmington, CT, USA.},
doi = {10.1002/mgg3.354},
pmid = {29271092},
pmcid = {PMC5902398},
language = {English},
read = {Yes},
rating = {0},
date-added = {2018-01-02T15:30:09GMT},
date-modified = {2018-01-02T15:30:59GMT},
abstract = {BACKGROUND:Genetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients. Increasingly, testing utilizing high throughput sequencing, including gene panels and whole exome sequencing, are offered as well.
METHODS:We performed genetic testing including microarray, fragile X testing and targeted gene panel, consistently sequencing 161 genes associated with ASD risk, in a clinical population of 100 well characterized children with ASD. Frequency of rare variants identified in individual genes was compared with that reported in the Exome Aggregation Consortium (ExAC) database.
RESULTS:We did not diagnose any conditions with complete penetrance for ASD; however, copy number variants believed to contribute to ASD risk were identified in 12%. Eleven children were found to have likely pathogenic variants on gene panel, yet, after careful analysis, none was considered likely causative of disease. KIRREL3 variants were identified in 6.7% of children compared to 2% in ExAC, suggesting a potential role for KIRREL3 variants in ASD risk. Children with KIRREL3 variants more often had minor facial dysmorphism and intellectual disability. We also observed an increase in rare variants in TSC2. However, analysis of variant data from the Simons Simplex Collection indicated that rare variants in TSC2 occur more commonly in specific racial/ethnic groups, which are more prevalent in our population than in the ExAC database.
CONCLUSION:The yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large-scale genomic databases used to identify variants that contribute to disease risk.},
url = {http://doi.wiley.com/10.1002/mgg3.354},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/A8/A8488AFB-B775-4B95-88FE-04108D090CC3.pdf},
file = {{A8488AFB-B775-4B95-88FE-04108D090CC3.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/A8/A8488AFB-B775-4B95-88FE-04108D090CC3.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1002/mgg3.354}}
}

@article{Oran:2016ir,
author = {Oran, Amanda R and Adams, Clare M and Zhang, Xiao-Yong and Gennaro, Victoria J and Pfeiffer, Harla K and Mellert, Hestia S and Seidel, Hans E and Mascioli, Kirsten and Kaplan, Jordan and Gaballa, Mahmoud R and Shen, Chen and Rigoutsos, Isidore and King, Michael P and Cotney, Justin L and Arnold, Jamie J and Sharma, Suresh D and Martinez-Outschoorn, Ubaldo E and Vakoc, Christopher R and Chodosh, Lewis A and Thompson, James E and Bradner, James E and Cameron, Craig E and Shadel, Gerald S and Eischen, Christine M and McMahon, Steven B},
title = {{Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer.}},
journal = {Oncotarget},
year = {2016},
volume = {7},
number = {45},
pages = {72395--72414},
month = aug,
publisher = {Impact Journals},
affiliation = {Departments of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.},
doi = {10.18632/oncotarget.11718},
pmid = {27590350},
pmcid = {PMC5340124},
language = {English},
read = {Yes},
rating = {0},
date-added = {2016-11-18T14:37:02GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors.},
url = {http://www.oncotarget.com/abstract/11718},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/BE/BE67FDBC-DB0D-449C-8A40-6B6D9166C362.pdf},
file = {{BE67FDBC-DB0D-449C-8A40-6B6D9166C362.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/BE/BE67FDBC-DB0D-449C-8A40-6B6D9166C362.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.18632/oncotarget.11718}}
}

@article{Reilly:vz,
author = {Reilly, Steven K and Yin, Jun and Ayoub, Albert E and Emera, Deena and Leng, Jing and Cotney, Justin and Sarro, Richard and Rakic, Pasko and Noonan, James P},
title = {{Evolutionary genomics. Evolutionary changes in promoter and enhancer activity during human corticogenesis.}},
journal = {Science (New York, NY)},
year = {2015},
volume = {347},
number = {6226},
pages = {1155--1159},
month = mar,
affiliation = {Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.},
doi = {10.1126/science.1260943},
pmid = {25745175},
pmcid = {PMC4426903},
language = {English},
read = {Yes},
rating = {0},
date-added = {2015-01-12T16:05:21GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Human higher cognition is attributed to the evolutionary expansion and elaboration of the human cerebral cortex. However, the genetic mechanisms contributing to these developmental changes are poorly understood. We used comparative epigenetic profiling of human, rhesus macaque, and mouse corticogenesis to identify promoters and enhancers that have gained activity in humans. These gains are significantly enriched in modules of coexpressed genes in the cortex that function in neuronal proliferation, migration, and cortical-map organization. Gain-enriched modules also showed correlated gene expression patterns and similar transcription factor binding site enrichments in promoters and enhancers, suggesting that they are connected by common regulatory mechanisms. Our results reveal coordinated patterns of potential regulatory changes associated with conserved developmental processes during corticogenesis, providing insight into human cortical evolution.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25745175&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/D1/D12C4D60-B88F-4934-A774-E458F902ED27.pdf},
file = {{D12C4D60-B88F-4934-A774-E458F902ED27.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/D1/D12C4D60-B88F-4934-A774-E458F902ED27.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1126/science.1260943}}
}

@article{Cotney:2015jz,
author = {Cotney, Justin L and Noonan, James P},
title = {{Chromatin immunoprecipitation with fixed animal tissues and preparation for high-throughput sequencing.}},
journal = {Cold Spring Harbor protocols},
year = {2015},
volume = {2015},
number = {2},
pages = {191--199},
month = feb,
affiliation = {Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520.},
doi = {10.1101/pdb.prot084848},
pmid = {25646502},
language = {English},
read = {Yes},
rating = {0},
date-added = {2015-02-09T16:26:52GMT},
date-modified = {2019-02-22T18:35:41GMT},
abstract = {Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) is a powerful method used to identify genome-wide binding patterns of transcription factors and distribution of various histone modifications associated with different chromatin states. In most published studies, ChIP-Seq has been performed on cultured cells grown under controlled conditions, allowing generation of large amounts of material in a homogeneous biological state. Although such studies have provided great insight into the dynamic landscapes of animal genomes, they do not allow the examination of transcription factor binding and chromatin states in adult tissues, developing embryonic structures, or tumors. Such knowledge is critical to understanding the information required to create and maintain a complex biological tissue and to identify noncoding regions of the genome directly involved in tissues affected by complex diseases such as autism. Studying these tissue types with ChIP-Seq can be challenging due to the limited availability of tissues and the lack of complex biological states able to be achieved in culture. These inherent differences require alterations of standard cross-linking and chromatin extraction typically used in cell culture. Here we describe a general approach for using small amounts of animal tissue to perform ChIP-Seq directed at histone modifications and transcription factors. Tissue is homogenized before treatment with formaldehyde to ensure proper cross-linking, and a two-step nuclear isolation is performed to increase extraction of soluble chromatin. Small amounts of soluble chromatin are then used for immunoprecipitation (IP) and prepared for multiplexed high-throughput sequencing.},
url = {http://www.cshprotocols.org/lookup/doi/10.1101/pdb.prot084848},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Articles/2015/Cotney/Cold_Spring_Harb_Protoc_2015_Cotney.pdf},
file = {{Cold_Spring_Harb_Protoc_2015_Cotney.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Articles/2015/Cotney/Cold_Spring_Harb_Protoc_2015_Cotney.pdf:application/pdf;Cold_Spring_Harb_Protoc_2015_Cotney.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Articles/2015/Cotney/Cold_Spring_Harb_Protoc_2015_Cotney.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1101/pdb.prot084848}}
}

@article{Cotney:wt,
author = {Cotney, Justin and Muhle, Rebecca A and Sanders, Stephan J and Liu, Li and Willsey, A Jeremy and Niu, Wei and Liu, Wenzhong and Klei, Lambertus and Lei, Jing and Yin, Jun and Reilly, Steven K and Tebbenkamp, Andrew T and Bichsel, Candace and Pletikos, Mihovil and {\v{S}}estan, Nenad and Roeder, Kathryn and State, Matthew W and Devlin, Bernie and Noonan, James P},
title = {{The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.}},
journal = {Nature Communications},
year = {2015},
volume = {6},
pages = {6404},
affiliation = {1] Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA [2] Kavli Institute for Neuroscience, Yale School of Medicine, PO Box 208001, New Haven, Connecticut 06520, USA.},
doi = {10.1038/ncomms7404},
pmid = {25752243},
pmcid = {PMC4355952},
language = {English},
read = {Yes},
rating = {0},
date-added = {2015-01-12T15:57:13GMT},
date-modified = {2019-02-22T18:35:41GMT},
abstract = {Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.},
url = {http://www.nature.com/doifinder/10.1038/ncomms7404},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/A8/A87506C3-CD07-49F4-BF94-0441235C4B24.pdf},
file = {{A87506C3-CD07-49F4-BF94-0441235C4B24.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/A8/A87506C3-CD07-49F4-BF94-0441235C4B24.pdf:application/pdf;A87506C3-CD07-49F4-BF94-0441235C4B24.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/A8/A87506C3-CD07-49F4-BF94-0441235C4B24.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1038/ncomms7404}}
}

@article{Willsey:2013bd,
author = {Willsey, A Jeremy and Sanders, Stephan J and Li, Mingfeng and Dong, Shan and Tebbenkamp, Andrew T and Muhle, Rebecca A and Reilly, Steven K and Lin, Leon and Fertuzinhos, Sofia and Miller, Jeremy A and Murtha, Michael T and Bichsel, Candace and Niu, Wei and Cotney, Justin and Ercan-Sencicek, A Gulhan and Gockley, Jake and Gupta, Abha R and Han, Wenqi and He, Xin and Hoffman, Ellen J and Klei, Lambertus and Lei, Jing and Liu, Wenzhong and Liu, Li and Lu, Cong and Xu, Xuming and Zhu, Ying and Mane, Shrikant M and Lein, Ed S and Wei, Liping and Noonan, James P and Roeder, Kathryn and Devlin, Bernie and {\v{S}}estan, Nenad and State, Matthew W},
title = {{Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.}},
journal = {Cell},
year = {2013},
volume = {155},
number = {5},
pages = {997--1007},
month = nov,
affiliation = {Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.},
doi = {10.1016/j.cell.2013.10.020},
pmid = {24267886},
pmcid = {PMC3995413},
language = {English},
read = {Yes},
rating = {0},
date-added = {2013-12-31T14:20:48GMT},
date-modified = {2017-10-13T13:43:19GMT},
abstract = {Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an~independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.},
url = {http://linkinghub.elsevier.com/retrieve/pii/S0092867413012968},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Articles/2013/Willsey/Cell_2013_Willsey.pdf},
file = {{Cell_2013_Willsey.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Articles/2013/Willsey/Cell_2013_Willsey.pdf:application/pdf;Cell_2013_Willsey.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Articles/2013/Willsey/Cell_2013_Willsey.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1016/j.cell.2013.10.020}}
}

@article{Demare:2013bn,
author = {Demare, Laura E and Leng, Jing and Cotney, Justin L and Reilly, Steven K and Yin, Jun and Sarro, Richard and Noonan, James P},
title = {{The genomic landscape of cohesin-associated chromatin interactions.}},
journal = {Genome research},
year = {2013},
volume = {23},
number = {8},
pages = {1224--1234},
month = aug,
annote = {10.1101/gr.156570.113},
affiliation = {Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA;},
doi = {10.1101/gr.156570.113},
pmid = {23704192},
pmcid = {PMC3730097},
language = {English},
read = {Yes},
rating = {0},
date-added = {2013-05-24T00:08:47GMT},
date-modified = {2017-10-13T13:45:40GMT},
abstract = {Cohesin is implicated in establishing tissue-specific DNA loops that target enhancers to promoters, and also localizes to sites bound by the insulator protein CTCF, which blocks enhancer-promoter communication. However, cohesin-associated interactions have not been characterized on a genome-wide scale. Here we performed chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) of the cohesin subunit SMC1A in developing mouse limb. We identified 2264 SMC1A interactions, of which 1491 (65%) involved sites co-occupied by CTCF. SMC1A participates in tissue-specific enhancer-promoter interactions and interactions that demarcate regions of correlated regulatory output. In contrast to previous studies, we also identified interactions between promoters and distal sites that are maintained in multiple tissues but are poised in embryonic stem cells and resolve to tissue-specific activated or repressed chromatin states in the mouse embryo. Our results reveal the diversity of cohesin-associated interactions in the genome and highlight their role in establishing the regulatory architecture of development.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=23704192&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2013/Demare/Demare_2013_Genome_Res.pdf},
file = {{Demare_2013_Genome_Res.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2013/Demare/Demare_2013_Genome_Res.pdf:application/pdf;Demare_2013_Genome_Res.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2013/Demare/Demare_2013_Genome_Res.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1101/gr.156570.113}}
}

@article{Cotney:2013ig,
author = {Cotney, Justin and Leng, Jing and Yin, Jun and Reilly, Steven K and DeMare, Laura E and Emera, Deena and Ayoub, Albert E and Rakic, Pasko and Noonan, James P},
title = {{The evolution of lineage-specific regulatory activities in the human embryonic limb.}},
journal = {Cell},
year = {2013},
volume = {154},
number = {1},
pages = {185--196},
month = jul,
affiliation = {Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.},
doi = {10.1016/j.cell.2013.05.056},
pmid = {23827682},
pmcid = {PMC3785101},
language = {English},
read = {Yes},
rating = {0},
date-added = {2013-05-21T14:16:14GMT},
date-modified = {2019-02-22T18:35:41GMT},
abstract = {The evolution of human anatomical features likely involved changes in gene regulation during development. However, the nature and extent of human-specific developmental regulatory functions remain unknown. We obtained a genome-wide view of cis-regulatory evolution in human embryonic tissues by comparing the histone modification H3K27ac, which provides a quantitative readout of promoter and enhancer activity, during human, rhesus, and mouse limb development. Based on increased H3K27ac, we find that 13% of promoters and 11% of enhancers have gained activity on the human lineage since the human-rhesus divergence. These gains largely arose by modification of ancestral regulatory activities in the limb or potential co-option from other tissues and are likely to have heterogeneous genetic causes. Most enhancers that exhibit gain of activity in humans originated in mammals. Gains at promoters and enhancers in the human limb are associated with increased gene expression, suggesting they include molecular drivers of human morphological evolution.},
url = {http://linkinghub.elsevier.com/retrieve/pii/S0092867413006995},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2013/Cotney/Cotney_2013_Cell.pdf},
file = {{Cotney_2013_Cell.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2013/Cotney/Cotney_2013_Cell.pdf:application/pdf;Cotney_2013_Cell.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2013/Cotney/Cotney_2013_Cell.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1016/j.cell.2013.05.056}}
}

@article{Clark:2013hs,
author = {Clark, Victoria E and Erson-Omay, E Zeynep and Serin, Akdes and Yin, Jun and Cotney, Justin and Ozduman, Koray and Av{\c s}ar, Timu{\c c}in and Li, Jie and Murray, Phillip B and Henegariu, Octavian and Yilmaz, Saliha and G{\"u}nel, Jennifer Moliterno and Carri{\'o}n-Grant, Geneive and Yilmaz, Baran and Grady, Conor and Tanrikulu, Bahattin and Bakircio{\u{g}}lu, Mehmet and Kaymak{\c c}alan, Hande and Caglayan, Ahmet Okay and Sencar, Leman and Ceyhun, Emre and Atik, A Fatih and Bayri, Ya{\c s}ar and Bai, Hanwen and Kolb, Luis E and Hebert, Ryan M and Omay, S Bulent and Mishra-Gorur, Ketu and Choi, Murim and Overton, John D and Holland, Eric C and Mane, Shrikant and State, Matthew W and Bilguvar, Kaya and Baehring, Joachim M and Gutin, Philip H and Piepmeier, Joseph M and Vortmeyer, Alexander and Brennan, Cameron W and Pamir, M Necmettin and Kili{\c c}, T{\"u}rker and Lifton, Richard P and Noonan, James P and Yasuno, Katsuhito and G{\"u}nel, Murat},
title = {{Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.}},
journal = {Science (New York, NY)},
year = {2013},
volume = {339},
number = {6123},
pages = {1077--1080},
month = mar,
publisher = {American Association for the Advancement of Science},
affiliation = {Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, USA.},
doi = {10.1126/science.1233009},
pmid = {23348505},
pmcid = {PMC4808587},
language = {English},
read = {Yes},
rating = {0},
date-added = {2013-03-25T19:58:46GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in {\textasciitilde}5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.},
url = {http://www.sciencemag.org/cgi/doi/10.1126/science.1233009},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2013/Clark/Clark_2013_Science.pdf},
file = {{Clark_2013_Science.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2013/Clark/Clark_2013_Science.pdf:application/pdf;Clark_2013_Science.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2013/Clark/Clark_2013_Science.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1126/science.1233009}}
}

@article{Bandyopadhyay:2013ea,
author = {Bandyopadhyay, Urmi and Cotney, Justin L and Nagy, Maria and Oh, Sunghee and Leng, Jing and Mahajan, Milind and Mane, Shrikant and Fenton, Wayne A and Noonan, James P and Horwich, Arthur L},
title = {{RNA-Seq Profiling of Spinal Cord Motor Neurons from a Presymptomatic SOD1 ALS Mouse.}},
journal = {PLoS ONE},
year = {2013},
volume = {8},
number = {1},
pages = {e53575},
affiliation = {Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America ; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America.},
doi = {10.1371/journal.pone.0053575},
pmid = {23301088},
pmcid = {PMC3536741},
language = {English},
read = {Yes},
rating = {0},
date-added = {2013-01-10T13:18:09GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Mechanisms involved with degeneration of motor neurons in amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) are poorly understood, but genetically inherited forms, comprising ∼10% of the cases, are potentially informative. Recent observations that several inherited forms of ALS involve the RNA binding proteins TDP43 and FUS raise the question as to whether RNA metabolism is generally disturbed in ALS. Here we conduct whole transcriptome profiling of motor neurons from a mouse strain, transgenic for a mutant human SOD1 (G85R SOD1-YFP), that develops symptoms of ALS and paralyzes at 5-6 months of age. Motor neuron cell bodies were laser microdissected from spinal cords at 3 months of age, a time when animals were presymptomatic but showed aggregation of the mutant protein in many lower motor neuron cell bodies and manifested extensive neuromuscular junction morphologic disturbance in their lower extremities. We observed only a small number of transcripts with altered expression levels or splicing in the G85R transgenic compared to age-matched animals of a wild-type SOD1 transgenic strain. Our results indicate that a major disturbance of polyadenylated RNA metabolism does not occur in motor neurons of mutant SOD1 mice, suggesting that the toxicity of the mutant protein lies at the level of translational or post-translational effects.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=23301088&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2013/Bandyopadhyay/Bandyopadhyay_2013_PLoS_ONE.pdf},
file = {{Bandyopadhyay_2013_PLoS_ONE.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2013/Bandyopadhyay/Bandyopadhyay_2013_PLoS_ONE.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1371/journal.pone.0053575}}
}

@article{Cotney:2012kl,
author = {Cotney, Justin L and Leng, Jing and Oh, Sunghee and Demare, Laura E and Reilly, Steven K and Gerstein, Mark B and Noonan, James P},
title = {{Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb.}},
journal = {Genome research},
year = {2012},
volume = {22},
number = {6},
pages = {1069--1080},
month = jun,
affiliation = {Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA;},
doi = {10.1101/gr.129817.111},
pmid = {22421546},
pmcid = {PMC3371702},
language = {English},
read = {Yes},
rating = {0},
date-added = {2012-03-29T13:23:02GMT},
date-modified = {2019-02-22T18:35:41GMT},
abstract = {The regulatory elements that direct tissue-specific gene expression in the developing mammalian embryo remain largely unknown. Although chromatin profiling has proven to be a powerful method for mapping regulatory sequences in cultured cells, chromatin states characteristic of active developmental enhancers have not been directly identified in embryonic tissues. Here we use whole-transcriptome analysis coupled with genome-wide profiling of H3K27ac and H3K27me3 to map chromatin states and enhancers in mouse embryonic forelimb and hindlimb. We show that gene-expression differences between forelimb and hindlimb, and between limb and other embryonic cell types, are correlated with tissue-specific H3K27ac signatures at promoters and distal sites. Using H3K27ac profiles, we identified 28,377 putative enhancers, many of which are likely to be limb specific based on strong enrichment near genes highly expressed in the limb and comparisons with tissue-specific EP300 sites and known enhancers. We describe a chromatin state signature associated with active developmental enhancers, defined by high levels of H3K27ac marking, nucleosome displacement, hypersensitivity to sonication, and strong depletion of H3K27me3. We also find that some developmental enhancers exhibit components of this signature, including hypersensitivity, H3K27ac enrichment, and H3K27me3 depletion, at lower levels in tissues in which they are not active. Our results establish histone modification profiling as a tool for developmental enhancer discovery, and suggest that enhancers maintain an open chromatin state in multiple embryonic tissues independent of their activity level.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22421546&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2012/Cotney/Cotney_2012_Genome_Res.pdf},
file = {{Cotney_2012_Genome_Res.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2012/Cotney/Cotney_2012_Genome_Res.pdf:application/pdf;Cotney_2012_Genome_Res.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2012/Cotney/Cotney_2012_Genome_Res.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1101/gr.129817.111}}
}

@article{Raimundo:2012fv,
author = {Raimundo, Nuno and Song, Lei and Shutt, Timothy E and McKay, Sharen E and Cotney, Justin L and Guan, Min-Xin and Gilliland, Thomas C and Hohuan, David and Santos-Sacchi, Joseph and Shadel, Gerald S},
title = {{Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness.}},
journal = {Cell},
year = {2012},
volume = {148},
number = {4},
pages = {716--726},
month = feb,
affiliation = {Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.},
doi = {10.1016/j.cell.2011.12.027},
pmid = {22341444},
pmcid = {PMC3285425},
language = {English},
read = {Yes},
rating = {0},
date-added = {2012-03-29T13:22:30GMT},
date-modified = {2017-10-13T13:43:21GMT},
abstract = {Mitochondrial dysfunction causes poorly understood tissue-specific pathology stemming from primary defects in respiration, coupled with altered reactive oxygen species (ROS), metabolic signaling, and apoptosis. The A1555G mtDNA mutation that causes maternally inherited deafness disrupts mitochondrial ribosome function, in part, via increased methylation of the mitochondrial 12S rRNA by the methyltransferase mtTFB1. In patient-derived A1555G cells, we show that 12S rRNA hypermethylation causes ROS-dependent activation of AMP kinase and the proapoptotic nuclear transcription factor E2F1. This retrograde mitochondrial-stress relay is operative in vivo, as transgenic-mtTFB1 mice exhibit enhanced 12S rRNA methylation in multiple tissues, increased E2F1 and apoptosis in the stria vascularis and spiral ganglion neurons of the inner ear, and progressive E2F1-dependent hearing loss. This mouse mitochondrial disease model provides a robust platform for deciphering the complex tissue specificity of human mitochondrial-based disorders, as well as the precise pathogenic mechanism of maternally inherited deafness and its exacerbation by environmental factors.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22341444&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2012/Raimundo/Raimundo_2012_Cell.pdf},
file = {{Raimundo_2012_Cell.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2012/Raimundo/Raimundo_2012_Cell.pdf:application/pdf;Raimundo_2012_Cell.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2012/Raimundo/Raimundo_2012_Cell.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1016/j.cell.2011.12.027}}
}

@article{Surovtseva:2011cq,
author = {Surovtseva, Yulia V and Shutt, Timothy E and Cotney, Justin L and Cimen, Huseyin and Chen, Sophia Y and Koc, Emine C and Shadel, Gerald S},
title = {{Mitochondrial ribosomal protein L12 selectively associates with human mitochondrial RNA polymerase to activate transcription.}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2011},
volume = {108},
number = {44},
month = nov,
affiliation = {Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.},
doi = {10.1073/pnas.1108852108},
pmid = {22003127},
pmcid = {PMC3207702},
language = {English},
read = {Yes},
rating = {0},
date-added = {2011-10-26T14:08:37GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Basal transcription of human mitochondrial DNA (mtDNA) in vitro requires the single-subunit, bacteriophage-related RNA polymerase, POLRMT, and transcription factor h-mtTFB2. This two-component system is activated differentially at mtDNA promoters by human mitochondrial transcription factor A (h-mtTFA). Mitochondrial ribosomal protein L7/L12 (MRPL12) binds directly to POLRMT, but whether it does so in the context of the ribosome or as a "free" protein in the matrix is unknown. Furthermore, existing evidence that MRPL12 activates mitochondrial transcription derives from overexpression studies in cultured cells and transcription experiments using crude mitochondrial lysates, precluding direct effects of MRPL12 on transcription to be assigned. Here, we report that depletion of MRPL12 from HeLa cells by shRNA results in decreased steady-state levels of mitochondrial transcripts, which are not accounted for by changes in RNA stability. We also show that a significant "free" pool of MRPL12 exists in human mitochondria not associated with ribosomes. "Free" MRPL12 binds selectively to POLRMT in vivo in a complex distinct from those containing h-mtTFB2. Finally, using a fully recombinant mitochondrial transcription system, we demonstrate that MRPL12 stimulates promoter-dependent and promoter-independent transcription directly in vitro. Based on these results, we propose that, when not associated with ribosomes, MRPL12 has a second function in transcription, perhaps acting to facilitate the transition from initiation to elongation. We speculate that this is one mechanism to coordinate mitochondrial ribosome biogenesis and transcription in human mitochondria, where transcription of rRNAs from the mtDNA presumably needs to be adjusted in accordance with the rate of import and assembly of the nucleus-encoded MRPs into ribosomes.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22003127&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2011/Surovtseva/Surovtseva_2011_Proc_Natl_Acad_Sci_USA.pdf},
file = {{Surovtseva_2011_Proc_Natl_Acad_Sci_USA.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2011/Surovtseva/Surovtseva_2011_Proc_Natl_Acad_Sci_USA.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1073/pnas.1108852108}}
}

@article{Ayoub:2011hj,
author = {Ayoub, Albert E and Oh, Sunghee and Xie, Yanhua and Leng, Jing and Cotney, Justin L and Dominguez, Martin H and Noonan, James P and Rakic, Pasko},
title = {{Transcriptional programs in transient embryonic zones of the cerebral cortex defined by high-resolution mRNA sequencing.}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2011},
volume = {108},
number = {36},
pages = {14950--14955},
month = sep,
affiliation = {Departments of Neurobiology and Genetics, Yale University School of Medicine, New Haven, CT 06520.},
doi = {10.1073/pnas.1112213108},
pmid = {21873192},
pmcid = {PMC3169109},
language = {English},
read = {Yes},
rating = {0},
date-added = {2011-10-03T21:21:47GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Characterizing the genetic programs that specify development and evolution of the cerebral cortex is a central challenge in neuroscience. Stem cells in the transient embryonic ventricular and subventricular zones generate neurons that migrate across the intermediate zone to the overlying cortical plate, where they differentiate and form the neocortex. It is clear that not one but a multitude of molecular pathways are necessary to progress through each cellular milestone, yet the underlying transcriptional programs remain unknown. Here, we apply differential transcriptome analysis on microscopically isolated cell populations, to define five transcriptional programs that represent each transient embryonic zone and the progression between these zones. The five transcriptional programs contain largely uncharacterized genes in addition to transcripts necessary for stem cell maintenance, neurogenesis, migration, and differentiation. Additionally, we found intergenic transcriptionally active regions that possibly encode unique zone-specific transcripts. Finally, we present a high-resolution transcriptome map of transient zones in the embryonic mouse forebrain.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=21873192&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2011/Ayoub/Ayoub_2011_Proc_Natl_Acad_Sci_USA.pdf},
file = {{Ayoub_2011_Proc_Natl_Acad_Sci_USA.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2011/Ayoub/Ayoub_2011_Proc_Natl_Acad_Sci_USA.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1073/pnas.1112213108}}
}

@article{Shutt:2010hr,
author = {Shutt, Timothy E and Lodeiro, Maria F and Cotney, Justin L and Cameron, Craig E and Shadel, Gerald S},
title = {{Core human mitochondrial transcription apparatus is a regulated two-component system in vitro.}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2010},
volume = {107},
number = {27},
pages = {12133--12138},
month = jul,
affiliation = {Department of Pathology, Yale University School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.},
doi = {10.1073/pnas.0910581107},
pmid = {20562347},
pmcid = {PMC2901451},
language = {English},
rating = {0},
date-added = {2010-10-28T13:24:40GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {The core human mitochondrial transcription apparatus is currently regarded as an obligate three-component system comprising the bacteriophage T7-related mitochondrial RNA polymerase, the rRNA methyltransferase-related transcription factor, h-mtTFB2, and the high mobility group box transcription/DNA-packaging factor, h-mtTFA/TFAM. Using a faithful recombinant human mitochondrial transcription system from Escherichia coli, we demonstrate that specific initiation from the mtDNA promoters, LSP and HSP1, only requires mitochondrial RNA polymerase and h-mtTFB2 in vitro. When h-mtTFA is added to these basal components, LSP exhibits a much lower threshold for activation and a larger amplitude response than HSP1. In addition, when LSP and HSP1 are together on the same transcription template, h-mtTFA-independent transcription from HSP1 and h-mtTFA-dependent transcription from both promoters is enhanced and a higher concentration of h-mtTFA is required to stimulate HSP1. Promoter competition experiments revealed that, in addition to LSP competing transcription components away from HSP1, additional cis-acting signals are involved in these aspects of promoter regulation. Based on these results, we speculate that the human mitochondrial transcription system may have evolved to differentially regulate transcription initiation and transcription-primed mtDNA replication in response to the amount of h-mtTFA associated with nucleoids, which could begin to explain the heterogeneity of nucleoid structure and activity in vivo. Furthermore, this study sheds new light on the evolution of mitochondrial transcription components by showing that the human system is a regulated two-component system in vitro, and thus more akin to that of budding yeast than thought previously.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=20562347&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/2010/Shutt/Shutt_2010_Proc_Natl_Acad_Sci_USA.pdf},
file = {{Shutt_2010_Proc_Natl_Acad_Sci_USA.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/2010/Shutt/Shutt_2010_Proc_Natl_Acad_Sci_USA.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1073/pnas.0910581107}}
}

@article{Cotney:2009kk,
author = {Cotney, Justin L and McKay, Sharen E and Shadel, Gerald S},
title = {{Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness.}},
journal = {Human molecular genetics},
year = {2009},
volume = {18},
number = {14},
pages = {2670--2682},
month = jul,
affiliation = {Department of Pathology, Yale University School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.},
doi = {10.1093/hmg/ddp208},
pmid = {19417006},
pmcid = {PMC2701340},
language = {English},
read = {Yes},
rating = {0},
date-added = {2009-05-27T16:06:53GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Mitochondrial biogenesis is controlled by signaling networks that relay information to and from the organelles. However, key mitochondrial factors that mediate such pathways and how they contribute to human disease are not understood fully. Here we demonstrate that the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 are key downstream effectors of mitochondrial biogenesis that perform unique, yet cooperative functions. The primary function of h-mtTFB2 is mtDNA transcription and maintenance, which is independent of its rRNA methyltransferase activity, while that of h-mtTFB1 is mitochondrial 12S rRNA methylation needed for normal mitochondrial translation, metabolism and cell growth. Over-expression of h-mtTFB1 causes 12S rRNA hypermethylation, aberrant mitochondrial biogenesis and increased sorbitol-induced cell death. These phenotypes are recapitulated in cells harboring the pathogenic A1555G mtDNA mutation, implicating a deleterious rRNA methylation-dependent retrograde signal in maternally inherited deafness pathology and shedding significant insight into how h-mtTFB1 acts as a nuclear modifier of this disease.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=19417006&retmode=ref&cmd=prlinks},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/A8/A8081A92-9187-4D91-B638-3740D07D6921.pdf},
file = {{A8081A92-9187-4D91-B638-3740D07D6921.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/A8/A8081A92-9187-4D91-B638-3740D07D6921.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1093/hmg/ddp208}}
}

@article{Wang:2007bv,
author = {Wang, Zhibo and Cotney, Justin and Shadel, Gerald S},
title = {{Human mitochondrial ribosomal protein MRPL12 interacts directly with mitochondrial RNA polymerase to modulate mitochondrial gene expression.}},
journal = {Journal of biochemistry},
year = {2007},
volume = {282},
number = {17},
pages = {12610--12618},
month = apr,
publisher = {American Society for Biochemistry and Molecular Biology},
affiliation = {Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.},
doi = {10.1074/jbc.M700461200},
pmid = {17337445},
pmcid = {PMC2606046},
language = {English},
read = {Yes},
rating = {0},
date-added = {2009-05-04T17:12:48GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {The core human mitochondrial transcription machinery comprises a single subunit bacteriophage-related RNA polymerase, POLRMT, the high mobility group box DNA-binding protein h-mtTFA/TFAM, and two transcriptional co-activator proteins, h-mtTFB1 and h-mtTFB2 that also have rRNA methyltransferase activity. Recapitulation of specific initiation of transcription in vitro can be achieved by a complex of POL-RMT, h-mtTFA, and either h-mtTFB1 or h-mtTFB2. However, the nature of mitochondrial transcription complexes in vivo and the potential involvement of additional proteins in the transcription process in human mitochondria have not been extensively investigated. In Saccharomyces cerevisiae, transcription and translation are physically coupled via the formation of a multiprotein complex nucleated by the binding of Nam1p to the amino-terminal domain of mtRNA polymerase (Rpo41p). This model system paradigm led us to search for proteins that interact with POLRMT to regulate mitochondrial gene expression in humans. Using an affinity capture strategy to identify POL-RMT-binding proteins, we identified mitochondrial ribosomal protein L7/L12 (MRPL12) as a protein in HeLa mitochondrial extracts that interacts specifically with POLRMT in vitro. Purified recombinant MRPL12 binds to POLRMT and stimulates mitochondrial transcription activity in vitro, demonstrating that this interaction is both direct and functional. Finally, from HeLa cells that overexpress FLAG epitope-tagged MRPL12, increased steady-state levels of mtDNA-encoded transcripts are observed and MRPL12-POLRMT complexes can be co-immunoprecipitated, providing strong evidence that this interaction enhances mitochondrial transcription or RNA stability in vivo. We speculate that the MRPL12 interaction with POLRMT is likely part of a novel regulatory mechanism that coordinates mitochondrial transcription with translation and/or ribosome biogenesis during human mitochondrial gene expression.},
url = {http://www.jbc.org/lookup/doi/10.1074/jbc.M700461200},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/1F/1FAF5557-C3C5-48FA-82D8-4EA92173BFB6.pdf},
file = {{1FAF5557-C3C5-48FA-82D8-4EA92173BFB6.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/1F/1FAF5557-C3C5-48FA-82D8-4EA92173BFB6.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1074/jbc.M700461200}}
}

@article{Cotney:2007fg,
author = {Cotney, Justin and Wang, Zhibo and Shadel, Gerald S},
title = {{Relative abundance of the human mitochondrial transcription system and distinct roles for h-mtTFB1 and h-mtTFB2 in mitochondrial biogenesis and gene expression.}},
journal = {Nucleic Acids Research},
year = {2007},
volume = {35},
number = {12},
pages = {4042--4054},
affiliation = {Graduate Program in Genetics and Molecular Biology, Emory University School of Medicine, 440 Clifton Road N.E., Atlanta, Georgia 30322, USA.},
doi = {10.1093/nar/gkm424},
pmid = {17557812},
pmcid = {PMC1919481},
language = {English},
read = {Yes},
rating = {0},
date-added = {2009-05-04T17:13:35GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Human mitochondrial transcription requires the bacteriophage-related RNA polymerase, POLRMT, the mtDNA-binding protein, h-mtTFA/TFAM, and two transcription factors/rRNA methyltransferases, h-mtTFB1 and h-mtTFB2. Here, we determined the steady-state levels of these core transcription components and examined the consequences of purposeful elevation of h-mtTFB1 or h-mtTFB2 in HeLa cells. On a per molecule basis, we find an approximately 6-fold excess of POLRMT to mtDNA and approximately 3-fold more h-mtTFB2 than h-mtTFB1. We also estimate h-mtTFA at approximately 50 molecules/mtDNA, a ratio predicted to support robust transcription, but not to coat mtDNA. Consistent with a role for h-mtTFB2 in transcription and transcription-primed replication, increased mitochondrial DNA and transcripts result from its over-expression. This is accompanied by increased translation rates of most, but not all mtDNA-encoded proteins. Over-expression of h-mtTFB1 did not significantly influence these parameters, but did result in increased mitochondrial biogenesis. Furthermore, h-mtTFB1 mRNA and protein are elevated in response to h-mtTFB2 over-expression, suggesting the existence of a retrograde signal to the nucleus to coordinately regulate expression of these related factors. Altogether, our results provide a framework for understanding the regulation of human mitochondrial transcription in vivo and define distinct roles for h-mtTFB1 and h-mtTFB2 in mitochondrial biogenesis and gene expression that together likely fine-tune mitochondrial function.},
url = {https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkm424},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/44/442ACDF9-7ED6-4689-B350-A44344555ED7.pdf},
file = {{442ACDF9-7ED6-4689-B350-A44344555ED7.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/44/442ACDF9-7ED6-4689-B350-A44344555ED7.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1093/nar/gkm424}}
}

@article{Cotney:2006fia,
author = {Cotney, Justin and Shadel, Gerald S},
title = {{Evidence for an early gene duplication event in the evolution of the mitochondrial transcription factor B family and maintenance of rRNA methyltransferase activity in human mtTFB1 and mtTFB2.}},
journal = {Journal of molecular evolution},
year = {2006},
volume = {63},
number = {5},
pages = {707--717},
month = nov,
publisher = {Springer-Verlag},
affiliation = {Department of Pathology, Yale University School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.},
doi = {10.1007/s00239-006-0075-1},
pmid = {17031457},
language = {English},
rating = {0},
date-added = {2017-08-31T18:36:49GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Most metazoans have two nuclear genes encoding orthologues of the well-characterized Saccharomyces cerevisiae mitochondrial transcription factor B (sc-mtTFB). This class of transcription factors is homologous to the bacterial KsgA family of rRNA methyltransferases, which in Escherichia coli dimethylates adjacent adenine residues in a stem-loop of the 16S rRNA. This posttranscriptional modification is conserved in most metazoan cytoplasmic and mitochondrial rRNAs. Homo sapiens mitochondrial transcription factor B1 (h-mtTFB1) possesses this enzymatic activity, implicating it as a dual-function protein involved in mitochondrial transcription and translation. Here we demonstrate that h-mtTFB2 also has rRNA methyltransferase activity but is a less efficient enzyme than h-mtTFB1. In contrast, sc-mtTFB has no detectable rRNA methyltransferase activity, correlating with the lack of the corresponding modification in the mitochondrial rRNA of budding yeast. Based on these results, and reports that Drosophila melanogaster mtTFB1 and mtTFB2 do not have completely overlapping functions, we propose a model for human mtDNA regulation that takes into account h-mtTFB1 and h-mtTFB2 likely having partially redundant transcription factor and rRNA methyltransferase functions. Finally, phylogenetic analyses of this family of proteins strongly suggest that the presence of two mtTFB homologues in metazoans is the result of a gene duplication event that occurred early in eukaryotic evolution prior to the divergence of fungi and metazoans. This model suggests that, after the gene duplication event, differential selective pressures on the rRNA methyltransferase and transcription factor activities of mtTFB genes occurred, with extreme cases culminating in the loss of one of the paralogous genes in certain species.},
url = {http://link.springer.com/10.1007/s00239-006-0075-1},
local-url = {file://localhost/Users/jcotney/owncloud/Papers/Library.papers3/Files/85/8578AE15-4DB6-479B-B444-9B8D4B49C7F7.pdf},
file = {{8578AE15-4DB6-479B-B444-9B8D4B49C7F7.pdf:/Users/jcotney/owncloud/Papers/Library.papers3/Files/85/8578AE15-4DB6-479B-B444-9B8D4B49C7F7.pdf:application/pdf}},
uri = {\url{papers3://publication/doi/10.1007/s00239-006-0075-1}}
}

@article{Pezzementi:2003uka,
author = {Pezzementi, Leo and Johnson, Kimberly and Tsigelny, Igor and Cotney, Justin and Manning, Elizabeth and Barker, Andrew and Merritt, Sarah},
title = {{Amino acids defining the acyl pocket of an invertebrate cholinesterase.}},
journal = {Comparative biochemistry and physiology. Part B, Biochemistry {\&} molecular biology},
year = {2003},
volume = {136},
number = {4},
pages = {813--832},
month = dec,
affiliation = {Division of Science and Mathematics, Birmingham-Southern College, Box 549022, Birmingham, AL 35254, USA. lpezzeme@bsc.edu},
pmid = {14662305},
language = {English},
rating = {0},
date-added = {2017-08-31T18:36:33GMT},
date-modified = {2017-08-31T18:52:52GMT},
abstract = {Amphioxus (Branchiostoma floridae) cholinesterase 2 (ChE2) hydrolyzes acetylthiocholine (AsCh) almost exclusively. We constructed a homology model of ChE2 on the basis of Torpedo californica acetylcholinesterase (AChE) and found that the acyl pocket of the enzyme resembles that of Drosophila melanogaster AChE, which is proposed to be comprised of Phe330 (Phe290 in T. californica AChE) and Phe440 (Val400), rather than Leu328 (Phe288) and Phe330 (Phe290), as in vertebrate AChE. In ChE2, the homologous amino acids are Phe312 (Phe290) and Phe422 (Val400). To determine if these amino acids define the acyl pocket of ChE2 and its substrate specificity, and to obtain information about the hydrophobic subsite, partially comprised of Tyr352 (Phe330) and Phe353 (Phe331), we performed site-directed mutagenesis and in vitro expression. The aliphatic substitution mutant F312I ChE2 hydrolyzes AsCh preferentially but also butyrylthiocholine (BsCh), and the change in substrate specificity is due primarily to an increase in k(cat) for BsCh; K(m) and K(ss) are also altered. F422L and F422V produce enzymes that hydrolyze BsCh and AsCh equally due to an increase in k(cat) for BsCh and a decrease in k(cat) for AsCh. Our data suggest that Phe312 and Phe422 define the acyl pocket. We also screened mutants for changes in sensitivity to various inhibitors. Y352A increases the sensitivity of ChE2 to the bulky inhibitor ethopropazine. Y352A decreases inhibition by BW284c51, consistent with its role as part of the choline-binding site. Aliphatic replacement mutations produce enzymes that are more sensitive to inhibition by iso-OMPA, presumably by increasing access to the active site serine. Y352A, F353A and F353V make ChE2 considerably more resistant to inhibition by eserine and neostigmine, suggesting that binding of these aromatic inhibitors is mediated by pi-pi or cation-pi interactions at the hydrophobic site. Our results also provide information about the aromatic trapping of the active site histidine and the inactivation of ChE2 by sulfhydryl reagents.},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=14662305&retmode=ref&cmd=prlinks},
uri = {\url{papers3://publication/uuid/45C47747-6223-441A-9807-8FE0944BAA82}}
}