RNA-dependent dynamic histone acetylation regulates MCL1 alternative splicing.
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.
Department of Biochemistry and Medical Genetics, University of Manitoba, Manitoba Institute of Child Health, Winnipeg, Manitoba, R3E 3P4, Canada, Department of Biochemistry and Medical Genetics, University of Manitoba, Manitoba Institute of Cell Biology, Winnipeg, Manitoba, R3E0V9, Canada and Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.
Dilshad H
DH
Khan
Carolina
C
Gonzalez
Charlton
C
Cooper
Jian-Min
JM
Sun
Hou Yu
HY
Chen
Shannon
S
Healy
Wayne
W
Xu
Karen T
KT
Smith
Jerry L
JL
Workman
Etienne
E
Leygue
James R
JR
Davie
D000107:Acetylation; D017398:Alternative Splicing; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D002843:Chromatin; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C579095:MCL1 protein, human