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Calcium‐mediated epigenetic regulation of alternative splicing in cardiomyocytes (560.6)
Author(s) -
Sharma Alok,
Lou Hua
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.560.6
Subject(s) - alternative splicing , exon skipping , epigenetics , rna splicing , microbiology and biotechnology , gene knockdown , exon , biology , histone , gene , genetics , rna
In contrast to the well‐studied regulation of tissue‐ and developmental stage‐specific alternative splicing, the regulated alternative splicing changes in cells responding to environmental cues is poorly understood. Here we report our discovery of a previously unknown calcium‐mediated epigenetic program that regulates alternative splicing in mouse cardiomyocytes. We found that elevated calcium levels in cardiomyocytes induced by KCl‐mediated depolarization or caffeine treatment led to a robust and reversible skipping of several alternative exons in a CaMKII‐ and PKD‐dependent manner. We selected two genes that showed increased skipping, NF1 and KTN1, for mechanistic studies. We demonstrated that elevated calcium levels induce a translocation of class II HDACs from the cell nucleus to the cytoplasm leading to histone hyperacetylation throughout the gene body of these two genes. Transcriptional elongation rate analysis indicated a two‐fold increase of elongation rate for these genes (3.2 to 6.8 kb/min for NF1; 2.1 to 3.9 kb/min for KTN1) but not for a gene that showed no change in splicing. The depolarizaition induced skipping can be rescued by siRNA knockdown of histone acetyltransferase CBP or p300, or camptothecin treatment, which is used to slow down transcriptional elongation. These studies have revealed a hidden network of alternative splicing that is regulated epigenetically in cardiomyocytes. Grant Funding Source : NIH