title: Calcium-mediated histone modifications regulate alternative splicing in cardiomyocytes.
abstract: 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.
authors.affiliation: Department of Genetics and Genome Sciences.
authors.forename: Alok
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Genetics and Genome Sciences.
authors.forename: Hieu
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Department of Genetics and Genome Sciences.
authors.forename: Cuiyu
authors.initials: C
authors.lastname: Geng
authors.affiliation: Department of Genetics and Genome Sciences.
authors.forename: Melissa N
authors.initials: MN
authors.lastname: Hinman
authors.affiliation: Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, and.
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, and Center for RNA Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 hua.lou@case.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Lou
mesh_terms: D000107:Acetylation; D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D005091:Exons; D005786:Gene Expression Regulation / Q000502:physiology; D016514:Genes, Neurofibromatosis 1; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000096:biosynthesis / Q000235:genetics; D011189:Potassium Chloride / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050396:TRPP Cation Channels / Q000502:physiology; D061805:Transcription Elongation, Genetic
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006655:Histone Deacetylases; D006657:Histones; D025542:Neurofibromin 1; D011189:Potassium Chloride; D047428:Protein Kinase Inhibitors; D012319:RNA Polymerase II; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050396:TRPP Cation Channels
keywords: alternative splicing; calcium; cardiomyocytes; histone hyperacetylation; transcriptional elongation rate