PT  - JOURNAL ARTICLE
AU  - Emanuela Kerschbamer
AU  - Takshashila Tripathi
AU  - Serkan Erdin
AU  - Elisa Salviato
AU  - Francesca Di Leva
AU  - Endre Sebestyén
AU  - Michele Arnoldi
AU  - Matteo Benelli
AU  - James F. Gusella
AU  - Silvano Piazza
AU  - Francesca Demichelis
AU  - Michael E. Talkowski
AU  - Francesco Ferrari
AU  - Marta Biagioli
TI  - <em>CHD8</em> Suppression Impacts on Histone H3 Lysine 36 Trimethylation and Alters RNA Alternative Splicing
AID  - 10.1101/2020.03.14.992032
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.14.992032
4099  - http://biorxiv.org/content/early/2020/03/16/2020.03.14.992032.short
4100  - http://biorxiv.org/content/early/2020/03/16/2020.03.14.992032.full
AB  - Disruptive mutations in the chromodomain helicase DNA binding protein 8 (CHD8) have been recurrently associated with Autism Spectrum Disorders (ASD). In normal cellular physiology, CHD8 co-purifies with MLL1 and MOF transcriptional activation complex, with elongating RNAPII and directly binds to DNA promoters and enhancers regions, thus a regulatory role in transcriptional initiation and elongation could be postulated.Here we investigated how chromatin landscape reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. We interrogated transcriptionally active and repressed regions, as well as active and poised enhancers.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. Histone H3K36me3 reduction associated to CHD8-suppression does not functionally impact on global transcriptional levels, but correlated with altered alternative splicing patterns of ∼ 2000 protein coding genes implicated in “RNA splicing”, “mitotic cell cycle phase transition” and “mRNA processing”, especially affecting alternative first exon and exon skipping events.In summary, our results point toward broad molecular consequences of CHD8 suppression, implicating altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.