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.

CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing / Kerschbamer, Emanuela; Arnoldi, Michele; Tripathi, Takshashila; Pellegrini, Miguel; Maturi, Samuele; Erdin, Serkan; Salviato, Elisa; Di Leva, Francesca; Sebestyén, Endre; Dassi, Erik; Zarantonello, Giulia; Benelli, Matteo; Campos, Eric; Basson, M Albert; Gusella, James F; Gustincich, Stefano; Piazza, Silvano; Demichelis, Francesca; Talkowski, Michael E; Ferrari, Francesco; Biagioli, Marta. - In: NUCLEIC ACIDS RESEARCH. - ISSN 0305-1048. - 50:22(2022), pp. 12809-12828. [10.1093/nar/gkac1134]

CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing

Kerschbamer, Emanuela;Arnoldi, Michele;Tripathi, Takshashila;Pellegrini, Miguel;Di Leva, Francesca;Dassi, Erik;Benelli, Matteo;Piazza, Silvano;Demichelis, Francesca;Biagioli, Marta
Ultimo
2022-01-01

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.
2022
22
Kerschbamer, Emanuela; Arnoldi, Michele; Tripathi, Takshashila; Pellegrini, Miguel; Maturi, Samuele; Erdin, Serkan; Salviato, Elisa; Di Leva, Francesca; Sebestyén, Endre; Dassi, Erik; Zarantonello, Giulia; Benelli, Matteo; Campos, Eric; Basson, M Albert; Gusella, James F; Gustincich, Stefano; Piazza, Silvano; Demichelis, Francesca; Talkowski, Michael E; Ferrari, Francesco; Biagioli, Marta
CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing / Kerschbamer, Emanuela; Arnoldi, Michele; Tripathi, Takshashila; Pellegrini, Miguel; Maturi, Samuele; Erdin, Serkan; Salviato, Elisa; Di Leva, Francesca; Sebestyén, Endre; Dassi, Erik; Zarantonello, Giulia; Benelli, Matteo; Campos, Eric; Basson, M Albert; Gusella, James F; Gustincich, Stefano; Piazza, Silvano; Demichelis, Francesca; Talkowski, Michael E; Ferrari, Francesco; Biagioli, Marta. - In: NUCLEIC ACIDS RESEARCH. - ISSN 0305-1048. - 50:22(2022), pp. 12809-12828. [10.1093/nar/gkac1134]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/373807
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