Trbp regulates heart function through microRNA-mediated Sox6 repression

被引：50

作者：

Ding, Jian ^{[1
]}

Chen, Jinghai ^{[1
]}

Wang, Yanqun ^{[2
]}

Kataoka, Masaharu ^{[1
,3
]}

Ma, Lixin ^{[1
,4
]}

Zhou, Pingzhu ^{[1
]}

Hu, Xiaoyun ^{[1
]}

Lin, Zhiqiang ^{[1
]}

Nie, Mao ^{[1
,5
]}

Deng, Zhong-Liang ^{[5
]}

Pu, William T. ^{[1
,6
]}

Wang, Da-Zhi ^{[1
,6
]}

机构：

[1] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Cardiol, Boston, MA 02139 USA

[2] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[3] Keio Univ, Sch Med, Dept Cardiol, Tokyo, Japan

[4] Hubei Univ, Coll Life Sci, Wuhan, Peoples R China

[5] Chongqing Med Univ, Affiliated Hosp 2, Dept Orthopaed Surg, Chongqing, Peoples R China

[6] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 07期

基金：

美国国家卫生研究院;

关键词：

RNA-BINDING-PROTEIN; GENE-EXPRESSION; CARDIOMYOCYTE PROLIFERATION; CARDIAC-HYPERTROPHY; MUTATION; DICER; COEXISTENCE; ACTIVATION; CONDUCTION; MYOPATHY;

D O I：

10.1038/ng.3324

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：776 / +

页数：10

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