<i>CHD8</i> suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing
Emanuela Kerschbamer, Michele Arnoldi, Takshashila Tripathi, Miguel Pellegrini, Samuele Maturi, Serkan Erdin, Elisa Salviato, Francesca Di Leva, Endre Sebestyén, Erik Dassi, Giulia Zarantonello, Matteo Benelli, Eric I. Campos, M. Albert Basson, James F. Gusella, Stefano Gustincich, Silvano Piazza, Francesca Demichelis, Michael E. Talkowski, Francesco Ferrari, Marta Biagioli
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.