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Journal ArticleDOI

From neural development to cognition: unexpected roles for chromatin

01 May 2013-Nature Reviews Genetics (NIH Public Access)-Vol. 14, Iss: 5, pp 347-359
TL;DR: Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains.
Abstract: Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have revealed mutations in chromatin-modifying enzymes, such as chromatin remodellers and histone-modifying enzymes. Such studies are improving our understanding of the roles of these modifiers in human neurodevelopment, and this article discusses the emerging roles for several of these enzymes in development and disease.

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Citations
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Journal ArticleDOI
Silvia De Rubeis1, Xin-Xin He2, Arthur P. Goldberg1, Christopher S. Poultney1, Kaitlin E. Samocha3, A. Ercument Cicek2, Yan Kou1, Li Liu2, Menachem Fromer1, Menachem Fromer3, R. Susan Walker4, Tarjinder Singh5, Lambertus Klei6, Jack A. Kosmicki3, Shih-Chen Fu1, Branko Aleksic7, Monica Biscaldi8, Patrick Bolton9, Jessica M. Brownfeld1, Jinlu Cai1, Nicholas G. Campbell10, Angel Carracedo11, Angel Carracedo12, Maria H. Chahrour3, Andreas G. Chiocchetti, Hilary Coon13, Emily L. Crawford10, Lucy Crooks5, Sarah Curran9, Geraldine Dawson14, Eftichia Duketis, Bridget A. Fernandez15, Louise Gallagher16, Evan T. Geller17, Stephen J. Guter18, R. Sean Hill3, R. Sean Hill19, Iuliana Ionita-Laza20, Patricia Jiménez González, Helena Kilpinen, Sabine M. Klauck21, Alexander Kolevzon1, Irene Lee22, Jing Lei2, Terho Lehtimäki, Chiao-Feng Lin17, Avi Ma'ayan1, Christian R. Marshall4, Alison L. McInnes23, Benjamin M. Neale24, Michael John Owen25, Norio Ozaki7, Mara Parellada26, Jeremy R. Parr27, Shaun Purcell1, Kaija Puura, Deepthi Rajagopalan4, Karola Rehnström5, Abraham Reichenberg1, Aniko Sabo28, Michael Sachse, Stephen Sanders29, Chad M. Schafer2, Martin Schulte-Rüther30, David Skuse22, David Skuse31, Christine Stevens24, Peter Szatmari32, Kristiina Tammimies4, Otto Valladares17, Annette Voran33, Li-San Wang17, Lauren A. Weiss29, A. Jeremy Willsey29, Timothy W. Yu19, Timothy W. Yu3, Ryan K. C. Yuen4, Edwin H. Cook18, Christine M. Freitag, Michael Gill16, Christina M. Hultman34, Thomas Lehner35, Aarno Palotie24, Aarno Palotie36, Aarno Palotie3, Gerard D. Schellenberg17, Pamela Sklar1, Matthew W. State29, James S. Sutcliffe10, Christopher A. Walsh3, Christopher A. Walsh19, Stephen W. Scherer4, Michael E. Zwick37, Jeffrey C. Barrett5, David J. Cutler37, Kathryn Roeder2, Bernie Devlin6, Mark J. Daly24, Mark J. Daly3, Joseph D. Buxbaum1 
13 Nov 2014-Nature
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

2,228 citations

Journal ArticleDOI
James J. Lee1, Robbee Wedow2, Aysu Okbay3, Edward Kong4, Omeed Maghzian4, Meghan Zacher4, Tuan Anh Nguyen-Viet5, Peter Bowers4, Julia Sidorenko6, Julia Sidorenko7, Richard Karlsson Linnér3, Richard Karlsson Linnér8, Mark Alan Fontana5, Mark Alan Fontana9, Tushar Kundu5, Chanwook Lee4, Hui Li4, Ruoxi Li5, Rebecca Royer5, Pascal Timshel10, Pascal Timshel11, Raymond K. Walters4, Raymond K. Walters12, Emily A. Willoughby1, Loic Yengo6, Maris Alver7, Yanchun Bao13, David W. Clark14, Felix R. Day15, Nicholas A. Furlotte, Peter K. Joshi14, Peter K. Joshi16, Kathryn E. Kemper6, Aaron Kleinman, Claudia Langenberg15, Reedik Mägi7, Joey W. Trampush5, Shefali S. Verma17, Yang Wu6, Max Lam, Jing Hua Zhao15, Zhili Zheng18, Zhili Zheng6, Jason D. Boardman2, Harry Campbell14, Jeremy Freese19, Kathleen Mullan Harris20, Caroline Hayward14, Pamela Herd13, Pamela Herd21, Meena Kumari13, Todd Lencz22, Todd Lencz23, Jian'an Luan15, Anil K. Malhotra22, Anil K. Malhotra23, Andres Metspalu7, Lili Milani7, Ken K. Ong15, John R. B. Perry15, David J. Porteous14, Marylyn D. Ritchie17, Melissa C. Smart14, Blair H. Smith24, Joyce Y. Tung, Nicholas J. Wareham15, James F. Wilson14, Jonathan P. Beauchamp25, Dalton Conley26, Tõnu Esko7, Steven F. Lehrer27, Steven F. Lehrer28, Steven F. Lehrer29, Patrik K. E. Magnusson30, Sven Oskarsson31, Tune H. Pers10, Tune H. Pers11, Matthew R. Robinson32, Matthew R. Robinson6, Kevin Thom33, Chelsea Watson5, Christopher F. Chabris17, Michelle N. Meyer17, David Laibson4, Jian Yang6, Magnus Johannesson34, Philipp Koellinger8, Philipp Koellinger3, Patrick Turley12, Patrick Turley4, Peter M. Visscher6, Daniel J. Benjamin5, Daniel J. Benjamin27, David Cesarini27, David Cesarini33 
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

1,658 citations

Journal ArticleDOI
21 Nov 2013-Cell
TL;DR: It is shown that the patterns of ASD and ID risk genes are distinct, providing a biological framework for further investigating the pathophysiology of ASD.

917 citations

Journal ArticleDOI
TL;DR: Current understanding of the genetic architecture of ASD is reviewed and genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology are integrated.
Abstract: Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

650 citations

References
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Journal ArticleDOI
06 Sep 2012-Nature
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

13,548 citations

Journal ArticleDOI
10 Aug 2001-Science
TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Abstract: Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.

9,309 citations

Journal ArticleDOI
TL;DR: Improved genome-scale mapping of methylation allows us to evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences.
Abstract: DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.

4,799 citations

Journal ArticleDOI
TL;DR: This study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
Abstract: Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.

4,503 citations

Journal ArticleDOI
02 Aug 2007-Nature
TL;DR: The application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells is reported and it is shown that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms.
Abstract: We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences Lysine 4 and lysine 9 trimethylation marks imprinting control regions Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations

4,166 citations

Related Papers (5)
13 Nov 2014-Nature
Silvia De Rubeis, Xin-Xin He, Arthur P. Goldberg, Christopher S. Poultney, Kaitlin E. Samocha, A. Ercument Cicek, Yan Kou, Li Liu, Menachem Fromer, Menachem Fromer, R. Susan Walker, Tarjinder Singh, Lambertus Klei, Jack A. Kosmicki, Shih-Chen Fu, Branko Aleksic, Monica Biscaldi, Patrick Bolton, Jessica M. Brownfeld, Jinlu Cai, Nicholas G. Campbell, Angel Carracedo, Angel Carracedo, Maria H. Chahrour, Andreas G. Chiocchetti, Hilary Coon, Emily L. Crawford, Lucy Crooks, Sarah Curran, Geraldine Dawson, Eftichia Duketis, Bridget A. Fernandez, Louise Gallagher, Evan T. Geller, Stephen J. Guter, R. Sean Hill, R. Sean Hill, Iuliana Ionita-Laza, Patricia Jiménez González, Helena Kilpinen, Sabine M. Klauck, Alexander Kolevzon, Irene Lee, Jing Lei, Terho Lehtimäki, Chiao-Feng Lin, Avi Ma'ayan, Christian R. Marshall, Alison L. McInnes, Benjamin M. Neale, Michael John Owen, Norio Ozaki, Mara Parellada, Jeremy R. Parr, Shaun Purcell, Kaija Puura, Deepthi Rajagopalan, Karola Rehnström, Abraham Reichenberg, Aniko Sabo, Michael Sachse, Stephen Sanders, Chad M. Schafer, Martin Schulte-Rüther, David Skuse, David Skuse, Christine Stevens, Peter Szatmari, Kristiina Tammimies, Otto Valladares, Annette Voran, Li-San Wang, Lauren A. Weiss, A. Jeremy Willsey, Timothy W. Yu, Timothy W. Yu, Ryan K. C. Yuen, Edwin H. Cook, Christine M. Freitag, Michael Gill, Christina M. Hultman, Thomas Lehner, Aarno Palotie, Aarno Palotie, Aarno Palotie, Gerard D. Schellenberg, Pamela Sklar, Matthew W. State, James S. Sutcliffe, Christopher A. Walsh, Christopher A. Walsh, Stephen W. Scherer, Michael E. Zwick, Jeffrey C. Barrett, David J. Cutler, Kathryn Roeder, Bernie Devlin, Mark J. Daly, Mark J. Daly, Joseph D. Buxbaum