期刊
NUCLEIC ACIDS RESEARCH
卷 50, 期 22, 页码 12809-12828出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac1134
关键词
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资金
- Department CIBIO Institutional funding
- Autism Speaks
- Simons Foundation Autism Research Initiative
- National Institutes of Health
- Structured International Post-doc Program of SEMM (SI-POD) [GM061354, NS093200]
- AFM-TELETHON fellowship
- [21835]
CHD8 suppression leads to reduction in histone H3K36me3 peaks and altered alternative splicing patterns. The study also reveals a novel interaction between CHD8 and the splicing regulator hnRNPL, providing mechanistic insights into the CHD8 suppression-derived splicing phenotype.
Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 462 genes implicated in 'regulation of RNA splicing' and 'mRNA catabolic process'. Mass spectrometry analysis uncovered a novel interaction between CHD8 and the splicing regulator heterogeneous nuclear ribonucleoprotein L (hnRNPL), providing the first mechanistic insights to explain the CHD8 suppression-derived splicing phenotype, partly implicating SETD2, a H3K36me3 methyltransferase. In summary, our results point toward broad molecular consequences of CHD8 suppression, entailing altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.
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