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Omer Durak, Fan Gao, Yea Jin Kaeser-Woo, Richard Rueda, Anthony J Martorell, Alexi Nott, Carol Y Liu, L Ashley Watson, Li-Huei Tsai
De novo mutations in CHD8 are strongly associated with autism spectrum disorder, but the basic biology of CHD8 remains poorly understood. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that while Chd8 stimulates the transcription of cell cycle genes, it also precludes the induction of neural-specific genes by regulating the expression of PRC2 complex components...
October 3, 2016: Nature Neuroscience
Yuta Katayama, Masaaki Nishiyama, Hirotaka Shoji, Yasuyuki Ohkawa, Atsuki Kawamura, Tetsuya Sato, Mikita Suyama, Toru Takumi, Tsuyoshi Miyakawa, Keiichi I Nakayama
Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours. ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently identified many de novo mutations in a variety of genes in individuals with ASD, with CHD8, a gene encoding a chromatin remodeller, being most frequently affected. Whether CHD8 mutations are causative for ASD and how they might establish ASD traits have remained unknown...
September 7, 2016: Nature
Elliot S Stolerman, Brooke Smith, Alka Chaubey, Julie R Jones
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are highly heritable. De novo genomic alterations are considered an important cause of autism spectrum disorders. Recent research has shown that de novo loss-of-function mutations in the chromodomain helicase DNA-binding protein 8 (CHD8) gene are associated with an increased risk of ASD. We describe a single case of an intragenic deletion of exons 26-28 in the CHD8 gene in a patient with autism and global developmental delay...
April 2016: European Journal of Medical Genetics
Marta Smyk, Anna Poluha, Ilona Jaszczuk, Magdalena Bartnik, Joanna Bernaciak, Beata Nowakowska
Neurodevelopmental disorders have long been associated with chromosomal abnormalities, including microdeletions and microduplications. Submicroscopic 14q11.2 deletions involving the CHD8 and SUPT16H genes have been reported in patients with developmental delay (DD)/intellectual disability (ID) or autism spectrum disorders (ASDs) and/or macrocephaly. Recently, disruptive CHD8 mutations were described in patients with similar phenotypes further showing pivotal role of CHD8 gene in the pathogenesis of DD/ID or ASDs...
May 2016: American Journal of Medical Genetics. Part A
Maud de Dieuleveult, Kuangyu Yen, Isabelle Hmitou, Arnaud Depaux, Fayçal Boussouar, Daria Bou Dargham, Sylvie Jounier, Hélène Humbertclaude, Florence Ribierre, Céline Baulard, Nina P Farrell, Bongsoo Park, Céline Keime, Lucie Carrière, Soizick Berlivet, Marta Gut, Ivo Gut, Michel Werner, Jean-François Deleuze, Robert Olaso, Jean-Christophe Aude, Sophie Chantalat, B Franklin Pugh, Matthieu Gérard
ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller-nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription...
February 4, 2016: Nature
Nancy Merner, Baudouin Forgeot d'Arc, Scott C Bell, Gilles Maussion, Huashan Peng, Julie Gauthier, Liam Crapper, Fadi F Hamdan, Jacques L Michaud, Laurent Mottron, Guy A Rouleau, Carl Ernst
Mutations in chromodomain helicase DNA-binding domain 8 (CHD8) have been identified in independent genotyping studies of autism spectrum disorder. To better understand the phenotype associated with CHD8 mutations, we genotyped all CHD8 exons in carefully assessed cohorts of autism (n = 142), schizophrenia (SCZ; n = 143), and intellectual disability (ID; n = 94). We identified one frameshift mutation, seven non-synonymous variants, and six synonymous variants. The frameshift mutation, p.Asn2092Lysfs*2, which creates a premature stop codon leading to the loss of 212 amino acids of the protein, was from an autism case on whom we present multiple clinical assessments and pharmacological treatments spanning more than 10 years...
May 2016: American Journal of Medical Genetics. Part A
Minggang Fang, Lloyd Hutchinson, April Deng, Michael R Green
During cancer development, it is well established that many genes, including tumor suppressor genes, are hypermethylated and transcriptionally repressed, a phenomenon referred to as epigenetic silencing. In general, the factors involved in, and the mechanistic basis of, epigenetic silencing during cancer development are not well understood. We have recently described an epigenetic silencing pathway, directed by the oncogenic B-Raf proto-oncogene (BRAF) variant BRAF(V600E), that mediates widespread epigenetic silencing in colorectal cancer (CRC)...
February 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
(no author information available yet)
BRD4-mediated transactivation activity in AML depends upon its interaction with NSD3-short.
January 2016: Cancer Discovery
Chen Shen, Jonathan J Ipsaro, Junwei Shi, Joseph P Milazzo, Eric Wang, Jae-Seok Roe, Yutaka Suzuki, Darryl J Pappin, Leemor Joshua-Tor, Christopher R Vakoc
The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain...
December 17, 2015: Molecular Cell
Jennifer R Shingleton, Michael T Hemann
Aberrant chromatin regulation is a frequent driver of leukemogenesis. Mutations in chromatin regulators often result in more stem-like cells that seed a bulk leukemic population. Inhibitors targeting these proteins represent an emerging class of therapeutics, and identifying further chromatin regulators that promote disease progression may result in additional drug targets. We identified the chromatin-modifying protein CHD8 as necessary for cell survival in a mouse model of BCR-Abl+ B-cell acute lymphoblastic leukemia...
2015: PloS One
Stephan J Sanders
Rapid progress in identifying the genes underlying autism spectrum disorder (ASD) has provided the substrate for a first wave of analyses into the underlying neurobiology. This review describes the consensus across these diverse analyses, highlighting two distinct sets of genes: 1) Genes that regulate chromatin and transcription, especially in cortical projection neurons and striatal medium spiny neurons during mid-fetal development; and 2) Genes involved in synapse development and function, especially during infancy and early childhood, and differentially expressed in the post mortem ASD brain...
August 2015: Current Opinion in Genetics & Development
Ping Wang, Mingyan Lin, Erika Pedrosa, Anastasia Hrabovsky, Zheng Zhang, Wenjun Guo, Herbert M Lachman, Deyou Zheng
BACKGROUND: Disruptive mutation in the CHD8 gene is one of the top genetic risk factors in autism spectrum disorders (ASDs). Previous analyses of genome-wide CHD8 occupancy and reduced expression of CHD8 by shRNA knockdown in committed neural cells showed that CHD8 regulates multiple cell processes critical for neural functions, and its targets are enriched with ASD-associated genes. METHODS: To further understand the molecular links between CHD8 functions and ASD, we have applied the CRISPR/Cas9 technology to knockout one copy of CHD8 in induced pluripotent stem cells (iPSCs) to better mimic the loss-of-function status that would exist in the developing human embryo prior to neuronal differentiation...
2015: Molecular Autism
Lőrinc Pongor, Máté Kormos, Christos Hatzis, Lajos Pusztai, András Szabó, Balázs Győrffy
BACKGROUND: The use of somatic mutations for predicting clinical outcome is difficult because a mutation can indirectly influence the function of many genes, and also because clinical follow-up is sparse in the relatively young next generation sequencing (NGS) databanks. Here we approach this problem by linking sequence databanks to well annotated gene-chip datasets, using a multigene transcriptomic fingerprint as a link between gene mutations and gene expression in breast cancer patients...
2015: Genome Medicine
Gilles Maussion, Alpha B Diallo, Carolina O Gigek, Elizabeth S Chen, Liam Crapper, Jean-Francois Théroux, Gary G Chen, Cristina Vasuta, Carl Ernst
Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs, SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs...
October 2015: Human Genetics
B Wilkinson, N Grepo, B L Thompson, J Kim, K Wang, O V Evgrafov, W Lu, J A Knowles, D B Campbell
Chromodomain helicase DNA-binding protein 8 (CHD8) was identified as a leading autism spectrum disorder (ASD) candidate gene by whole-exome sequencing and subsequent targeted-sequencing studies. De novo loss-of-function mutations were identified in 12 individuals with ASD and zero controls, accounting for a highly significant association. Small interfering RNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA sequencing revealed that CHD8 insufficiency results in altered expression of 1715  genes, including both protein-coding and noncoding RNAs...
2015: Translational Psychiatry
Niklas Krumm, Tychele N Turner, Carl Baker, Laura Vives, Kiana Mohajeri, Kali Witherspoon, Archana Raja, Bradley P Coe, Holly A Stessman, Zong-Xiao He, Suzanne M Leal, Raphael Bernier, Evan E Eichler
To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14, P = 0.0002) in comparison to unaffected siblings, an effect involving significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kb), maternally inherited events (P = 0...
June 2015: Nature Genetics
María Ceballos-Chávez, Alicia Subtil-Rodríguez, Eugenia G Giannopoulou, Daniel Soronellas, Elena Vázquez-Chávez, Guillermo P Vicent, Olivier Elemento, Miguel Beato, José C Reyes
While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1...
April 2015: PLoS Genetics
Roger Higdon, Rachel K Earl, Larissa Stanberry, Caitlin M Hudac, Elizabeth Montague, Elizabeth Stewart, Imre Janko, John Choiniere, William Broomall, Natali Kolker, Raphael A Bernier, Eugene Kolker
Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes...
April 2015: Omics: a Journal of Integrative Biology
Justin Cotney, Rebecca A Muhle, Stephan J Sanders, Li Liu, A Jeremy Willsey, Wei Niu, Wenzhong Liu, Lambertus Klei, Jing Lei, Jun Yin, Steven K Reilly, Andrew T Tebbenkamp, Candace Bichsel, Mihovil Pletikos, Nenad Sestan, Kathryn Roeder, Matthew W State, Bernie Devlin, James P Noonan
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...
2015: Nature Communications
Nathan A Damaschke, Bing Yang, Michael L Blute, Chee Paul Lin, Wei Huang, David F Jarrard
Abnormal expression and function of chromatin regulators results in the altered chromatin structure seen in cancer. The chromatin regulator CTCF, its cofactor CHD8, and antagonistic paralogue BORIS have wide-ranging effects on gene regulation. Their concurrent expression and regulation was examined in benign, localized, and metastatic prostate cancer (PCa) arrays with extended follow-up using an automated quantitative imaging system, VECTRA. Epithelial staining was quantified and compared against a range of clinicopathologic variables...
December 2014: Neoplasia: An International Journal for Oncology Research
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