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http://www.nature.com/nature/journal/v515/n7526/full/nature13772.html

FRA ABSTRACT: 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.
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http://www.nature.com/articles/ncomms7404
FRA ABSTRACT: 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. –

two recent developments have sparked rapid progress in ASD gene discovery. First, it is now appreciated that de novo mutations contribute to ASD and often carry large effects5,6,7,8. Second, the advent of next-generation sequencing technologies has enabled hypothesis-naïve whole-exome surveys of large ASD cohorts to identify genes with de novo, ASD-associated damaging mutations9,10,11,12. This approach allows the level of ASD risk to be assessed for all genes using uniform statistical and genetic criteria, providing a quantitative definition of an ASD risk gene independent of prior hypotheses regarding gene functions or disease processes.

nine such high-confidence13 ASD risk genes have been identified: ANK2, CHD8, CUL3, DYRK1A, GRIN2B, KATNAL2, POGZ, SCN2A and TBR1. These genes encode proteins with a variety of functions, including chromatin modification and transcriptional regulation14, suggesting molecular mechanisms perturbed in ASD. Of these genes, CHD8 has the largest number of loss of function mutations in individuals with ASD, and therefore the strongest association with ASD risk.

CHD8 encodes an ATP-dependent chromatin remodeller that binds to trimethylated histone H3 lysine 4, a post-translational histone modification present at active promoters17,18,19.

Other studies suggest CHD8 may repress Wnt/β-catenin target genes and p53-dependent apoptosis17,21. These findings, coupled with the strong genetic evidence described above, suggest that loss of CHD8 function contributes to ASD pathology by disrupting the expression of genes regulated by CHD8.

networks of genes that were co-expressed with the nine known high-confidence ASD risk genes at specific brain regions and points in time. To define a larger set of potential ASD risk genes, Willsey et al. identified 122 genes that had a de novo loss of function in a single individual with ASD, but not in matched controls. These potential ASD risk genes show the most significant co-expression with high-confidence ASD risk genes in midfetal prefrontal and primary motor-somatosensory cortex (PFC-MSC). A parallel study also supported the convergence of ASD risk genes in co-expression networks at this developmental time point and location22. These findings suggest ASD risk genes are co-regulated, and may thus converge in regulatory networks associated with ASD. Owing to its chromatin remodelling activity, its association with other transcriptional regulators, and its increased expression during human midfetal development15, CHD8 is a prime candidate for contributing to the organization of such networks by regulating other ASD risk genes.

are ASD risk genes overrepresented among genes targeted by CHD8 in the developing brain? Second, are CHD8 targets overrepresented in ASD-associated co-expression networks in midfetal human brain? Third, does loss of CHD8 result in dysregulation of ASD risk genes that are targeted by CHD8?

CHD8 gene targets are overrepresented in the ASD-associated co-expression network identified in human midfetal brain13, supporting the hypothesis that CHD8 is a key regulator of genes in this network. After downregulation of CHD8 expression in hNSCs, ASD risk genes bound by CHD8 in multiple neurodevelopmental contexts are significantly dysregulated by CHD8 loss.

CHD8 seems to be a direct regulator of other ASD risk genes during human brain development.
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[https://www.ncbi.nlm.nih.gov/pubmed/28255957 af Mastrototaro G, Zaghi M, Sessa A: link: https://link.springer.com/article/10.1007%2Fs12031-017-0900-6]
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https://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_es.html

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http://epigenie.com/epigenetics-in-autism-spectrum-disorders-with-dr-janine-lasalle/
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