RNA-dependent dynamic histone acetylation regulates MCL1 alternative splicing

Abstract

Histone deacetylases (HDACs) and lysine acetyltransferases (KATs) catalyze dynamic histone acetylation at regulatory and coding regions of transcribed genes. Highly phosphorylated HDAC2 is recruited within corepressor complexes to regulatory regions, while the nonphosphorylated form is associated with the gene body. In this study, we characterized the nonphosphorylated HDAC2 complexes recruited to the transcribed gene body and explored the function of HDAC-complex-mediated dynamic histone acetylation. HDAC1 and 2 were coimmunoprecipitated with several splicing factors, including serine/arginine-rich splicing factor 1 (SRSF1) which has roles in alternative splicing. The co-chromatin immunoprecipitation of HDAC1/2 and SRSF1 to the gene body was RNA-dependent. Inhibition of HDAC activity and knockdown of HDAC1, HDAC2 or SRSF1 showed that these proteins were involved in alternative splicing of MCL1. HDAC1/2 and KAT2B were associated with nascent pre-mRNA in general and with MCL1 pre-mRNA specifically. Inhibition of HDAC activity increased the occupancy of KAT2B and acetylation of H3 and H4 of the H3K4 methylated alternative MCL1 exon 2 nucleosome. Thus, nonphosphorylated HDAC1/2 is recruited to pre-mRNA by splicing factors to act at the RNA level with KAT2B and other KATs to catalyze dynamic histone acetylation of the MCL1 alternative exon and alter the splicing of MCL1 pre-mRNA.

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

“…ZFP318 binding to HDAC2 (21) is potentially similar to the recently demonstrated interaction between the RNA-binding protein HuR and HDAC2 to influence alternative mRNA splicing (34). A large amount of alternative splicing occurs cotranscriptionally when pre-mRNAs are still chromatin associated, where it is governed by two-way cooperation between RNA-binding splicing factors such as HuR or SRSF proteins, the extent of histone acetylation along intragenic chromatin, and the speed of RNA polymerase II (Pol II) transcript elongation along chromatin (34)(35)(36)(37)(38).…”

Alcohol-Mediated Missplicing of Mcl-1 Pre-mRNA is Involved in Neurotoxicity

“…Next we sought to investigate the effect of EtOH exposure on alternative splicing patterns of candidate genes which have been shown to be regulated by SRSF1 and involved in regulation of apoptosis. Among the possible candidate genes, we analyzed the alternative splicing of Bcl2-like protein 11 (BCL2L11 or BIM), macrophage-stimulating protein receptor (MST1R), bridging integrator 1 (BIN1), and myeloid cell leukemia 1 (Mcl-1) (Anczukow et al, 2012; Khan et al, 2014; Karni et al, 2007). SH-SY5Y cells were exposed to 50 mM EtOH for up to 8h.…”

Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

“…Additional accumulated evidence has associated histone acetylation with cotranscriptional splicing. Inhibition of HDAC1, HDAC2, or SRSF1 (the SR protein formerly known as SF2/ASF) expression results in alternative splicing of MCL1 (158). Further evidence was provided by a genome-wide study in which HDAC inhibition altered the splicing pattern of more than 700 genes and reduced cotranscriptional association of the splicing regulator SRSF5 (formerly known as SRp40) with its target exons (144).…”