期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：E4920-E4928
DOI：10.1073/pnas.1408964111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceCalcium is an important intracellular second messenger that regulates many biological processes. Many extracellular environmental cues lead to cellular calcium-level changes, which impact on the output of gene expression. In cardiomyocytes, calcium is known to control gene expression at the level of transcription, whereas its role in regulating alternative splicing has not been explored. Our studies demonstrate that in these cells a network of alternatively spliced exons exists, which responds to the altered calcium levels by changing their splicing patterns. Our studies further elucidate an epigenetic regulatory mechanism, triggered by calcium signaling pathways, that leads to histone hyperacetylation along gene bodies, which increases the transcriptional elongation rate of RNA polymerase II and impacts alternative splicing. In cardiomyocytes, calcium is known to control gene expression at the level of transcription, whereas its role in regulating alternative splicing has not been explored. Here we report that, in mouse primary or embryonic stem cell-derived cardiomyocytes, increased calcium levels induce robust and reversible skipping of several alternative exons from endogenously expressed genes. Interestingly, we demonstrate a calcium-mediated splicing regulatory mechanism that depends on changes of histone modifications. Specifically, the regulation occurs through changes in calcium-responsive kinase activities that lead to alterations in histone modifications and subsequent changes in the transcriptional elongation rate and exon skipping. We demonstrate that increased intracellular calcium levels lead to histone hyperacetylation along the body of the genes containing calcium-responsive alternative exons by disrupting the histone deacetylase-to-histone acetyltransferase balance in the nucleus. Consequently, the RNA polymerase II elongation rate increases significantly on those genes, resulting in skipping of the alternative exons. These studies reveal a mechanism by which calcium-level changes in cardiomyocytes impact on the output of gene expression through altering alternative pre-mRNA splicing patterns.
