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Nucleic Acids Res ; 50(22): 12809-12828, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36537238

RESUMO

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.


Assuntos
Processamento Alternativo , Caderinas , Histonas , Cromatina , Histonas/metabolismo , Lisina/metabolismo , RNA/metabolismo , Caderinas/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Transtorno do Espectro Autista/genética
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