{"doi":"10.1093/nar/gkac1134","title":"<i>CHD8</i> suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing","abstract":"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.","journal":"Nucleic Acids Research","year":2022,"id":250882,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":580836,"name":"Michele Arnoldi","orcid":null,"position":1,"is_corresponding":false},{"id":580391,"name":"Takshashila Tripathi","orcid":"0000-0001-6399-9825","position":2,"is_corresponding":false},{"id":893646,"name":"Miguel Pellegrini","orcid":null,"position":3,"is_corresponding":false},{"id":893647,"name":"Samuele Maturi","orcid":null,"position":4,"is_corresponding":false},{"id":352795,"name":"Serkan Erdin","orcid":"0000-0001-6587-2625","position":5,"is_corresponding":false},{"id":580392,"name":"Elisa Salviato","orcid":"0000-0003-3246-7820","position":6,"is_corresponding":false},{"id":580393,"name":"Francesca Di Leva","orcid":"0000-0002-6167-0679","position":7,"is_corresponding":false},{"id":580394,"name":"Endre Sebestyén","orcid":"0000-0001-5470-2161","position":8,"is_corresponding":false},{"id":17809,"name":"Erik Dassi","orcid":"0000-0003-4487-0449","position":9,"is_corresponding":false},{"id":893209,"name":"Giulia Zarantonello","orcid":"0000-0002-6742-9237","position":10,"is_corresponding":false},{"id":259319,"name":"Matteo Benelli","orcid":"0000-0003-1227-356X","position":11,"is_corresponding":false},{"id":893210,"name":"Eric I. 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