Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nucleic acids research, 2022-12, Vol.50 (22), p.12809

Ort / Verlag

England

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.