title: Rbm24 Regulates Alternative Splicing Switch in Embryonic Stem Cell Cardiac Lineage Differentiation.
abstract: The transition of embryonic stem cell (ESC) pluripotency to differentiation is accompanied by an expansion of mRNA and proteomic diversity. Post-transcriptional regulation of ESCs is critically governed by cell type-specific splicing. However, little is known about the splicing factors and the molecular mechanisms directing ESC early lineage differentiation. Our study identifies RNA binding motif protein 24 (Rbm24) as a key splicing regulator that plays an essential role in controlling post-transcriptional networks during ESC transition into cardiac differentiation. Using an inducible mouse ESC line in which gene expression could be temporally regulated, we demonstrated that forced expression of Rbm24 in ESCs dramatically induced a switch to cardiac specification. Genome-wide RNA sequencing analysis identified more than 200 Rbm24-regulated alternative splicing events (AS) which occurred in genes essential for the ESC pluripotency or differentiation. Remarkably, AS genes regulated by Rbm24 composed of transcriptional factors, cytoskeleton proteins, and ATPase gene family members which are critical components required for cardiac development and functionality. Furthermore, we show that Rbm24 regulates ESC differentiation by promoting alternative splicing of pluripotency genes. Among the Rbm24-regulated events, Tpm1, an actin filament family gene, was identified to possess ESC/tissue specific isoforms. We demonstrated that these isoforms were functionally distinct and that their exon AS switch was essential for ESC differentiation. Our results suggest that ESC's switching into the differentiation state can be initiated by a tissue-specific splicing regulator, Rbm24. This finding offers a global view on how an RNA binding protein influences ESC lineage differentiation by a splicing-mediated regulatory mechanism. Stem Cells 2016;34:1776-1789.
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.|ShenZhen Research Institute, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.|Department of Cardiology, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Zi Guan
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Li Yan
authors.initials: LY
authors.lastname: Guo
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Kong
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Meng Kai
authors.initials: MK
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Ying Hua
authors.initials: YH
authors.lastname: Lu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Zheng Rong
authors.initials: ZR
authors.lastname: Huang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Wei Hua
authors.initials: WH
authors.lastname: Li
authors.affiliation: Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Xiu Qin
authors.initials: XQ
authors.lastname: Xu
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D055785:Gene Knockdown Techniques; D016678:Genome; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: C000594453:RBM24 protein, human; D016601:RNA-Binding Proteins
keywords: Alternative splicing; Cardiac; Embryonic stem cell; RNA binding protein; Rbm24