title: Trbp regulates heart function through microRNA-mediated Sox6 repression.
abstract: Cardiomyopathy is associated with altered expression of genes encoding contractile proteins. Here we show that Trbp (Tarbp2), an RNA-binding protein, is required for normal heart function. Cardiac-specific inactivation in mice of Trbp (Trbp(cKO)) caused progressive cardiomyopathy and lethal heart failure. Loss of Trbp function resulted in upregulation of Sox6, repression of genes encoding normal cardiac slow-twitch myofiber proteins and pathologically increased expression of genes encoding skeletal fast-twitch myofiber proteins. Remarkably, knockdown of Sox6 fully rescued the Trbp-mutant phenotype, whereas mice overexpressing Sox6 phenocopied Trbp(cKO) mice. Trbp inactivation was mechanistically linked to Sox6 upregulation through altered processing of miR-208a, which is a direct inhibitor of Sox6. Transgenic overexpression of Mir208a sufficiently repressed Sox6, restored the balance in gene expression for fast- and slow-twitch myofiber proteins, and rescued cardiac function in Trbp(cKO) mice. Together, our studies identify a new Trbp-mediated microRNA-processing mechanism in the regulation of a linear genetic cascade essential for normal heart function.
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departmant of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yanqun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kataoka
authors.affiliation: 1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] College of Life Sciences, Hubei University, Wuhan, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Pingzhu
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: 1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Nie
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Deng
authors.affiliation: 1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.affiliation: 1] Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000502:physiology*; D055755:SOXD Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D035683:MicroRNAs; D016601:RNA-Binding Proteins; D055755:SOXD Transcription Factors; D000099253:Trans-Activation Responsive RNA-Binding Protein; C543978:Mirn208 microRNA, mouse; C095939:Sox6 protein, mouse