RNA-dependent dynamic histone acetylation regulates MCL1 alternative splicing

Area of Science:

• Molecular Biology
• Gene Regulation
• Epigenetics

Background:

• Histone deacetylases (HDACs) and lysine acetyltransferases (KATs) regulate gene transcription through dynamic histone acetylation.
• HDAC2 exists in phosphorylated (regulatory regions) and nonphosphorylated (gene body) forms, suggesting distinct functions.

Purpose of the Study:

• Characterize nonphosphorylated HDAC2 complexes in the gene body.
• Investigate the role of HDAC-complex-mediated histone acetylation in gene splicing.

Main Methods:

• Co-immunoprecipitation of HDAC1/2 with splicing factors like SRSF1.
• RNA-dependent co-chromatin immunoprecipitation.
• HDAC inhibition and gene knockdown experiments.
• Analysis of pre-mRNA association and histone acetylation levels.

Main Results:

• HDAC1/2 and SRSF1 associate with the gene body in an RNA-dependent manner.
• HDAC1, HDAC2, and SRSF1 are involved in the alternative splicing of MCL1.
• HDAC1/2 and KAT2B associate with nascent pre-mRNA, specifically MCL1 pre-mRNA.
• HDAC inhibition increases KAT2B occupancy and histone acetylation at the alternative MCL1 exon 2 nucleosome.

Conclusions:

• Nonphosphorylated HDAC1/2 is recruited to pre-mRNA by splicing factors.
• HDACs and KATs act at the RNA level to modulate histone acetylation and alternative splicing.
• This mechanism specifically impacts MCL1 alternative exon splicing.