Kerschbamer, Emanuela;
Arnoldi, Michele;
Tripathi, Takshashila;
Pellegrini, Miguel;
Maturi, Samuele;
Erdin, Serkan;
Salviato, Elisa;
... Biagioli, Marta; + view all
(2022)
CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing.
Nucleic Acids Research
, 50
(22)
pp. 12809-12828.
10.1093/nar/gkac1134.
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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.
| Type: | Article |
|---|---|
| Title: | CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/nar/gkac1134 |
| Publisher version: | https://doi.org/10.1093/nar/gkac1134 |
| Language: | English |
| Additional information: | © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10162290 |
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