MKRN3 regulates the epigenetic switch of mammalian puberty via ubiquitination of MBD3

被引：57

作者：

Li, Chuanyin ^{[1
,2
,3
]}

Lu, Wenli ^{[1
,2
]}

Yang, Liguang ^{[1
,2
,3
,4
]}

Li, Zhengwei ^{[1
,2
,3
]}

Zhou, Xiaoyi ^{[5
]}

Guo, Rong ^{[1
,2
,3
]}

Wang, Junqi ^{[1
,2
]}

Wu, Zhebao ^{[6
]}

Dong, Zhiya ^{[1
,2
]}

Ning, Guang ^{[7
,8
]}

Shi, Yujiang ^{[9
,10
]}

Gu, Yinmin ^{[11
]}

Chen, Peng ^{[1
,2
,3
]}

Hao, Zijian ^{[1
,2
,3
]}

Han, Tianting ^{[1
,2
,3
]}

Yang, Meiqiang ^{[1
,2
,3
]}

Wang, Wei ^{[1
,2
]}

Huang, Xuehui ^{[5
]}

Li, Yixue ^{[1
,2
,3
,4
]}

Gao, Shan ^{[11
]}

Hu, Ronggui ^{[1
,2
,3
,12
]}

机构：

[1] Shanghai Jiao Tong Univ, Dept Pediat, Ruijin Hosp, Sch Med, Shanghai 200025, Peoples R China

[2] Chinese Acad Sci, State Key Lab Mol Biol, CAS Ctr Excellence Mol Cell, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China

[3] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[4] Univ Chinese Acad Sci, CAS Key Lab Computat Biol, CAS MPG Partner Inst Computat Biol,Shanghai Inst, Shanghai Inst Biol Sci,Chinese Acad Sci, Shanghai 200031, Peoples R China

[5] Shanghai Normal Univ, Coll Life Sci, Shanghai 200234, Peoples R China

[6] Shanghai Jiao Tong Univ, Ruijin Hosp, Ctr Pituitary Tumor, Shanghai 200025, Peoples R China

[7] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Endocrine & Metab Dis, Shanghai Key Lab Endocrine Tumors, Shanghai 200025, Peoples R China

[8] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, E Inst Endocrinol, Shanghai 200025, Peoples R China

[9] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA

[10] Harvard Med Sch, Boston, MA 02115 USA

[11] Chinese Acad Sci, CAS Key Lab Biomed Diagnost, Suzhou Inst Biomed Engn & Technol, Suzhou 215163, Peoples R China

[12] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Canc Ctr, Shanghai 200072, Peoples R China

来源：

NATIONAL SCIENCE REVIEW | 2020年 / 7卷 / 03期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

ubiquitin; MKRN3; DNA methylation; MBD3; DNA demethylase; central precocious puberty; BINDING DOMAIN PROTEINS; DNA DEMETHYLATION; MECHANISMS; MUTATIONS; INDUCTION; GENES;

D O I：

10.1093/nsr/nwaa023

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Central precocious puberty (CPP) refers to a human syndrome of early puberty initiation with characteristic increase in hypothalamic production and release of gonadotropin-releasing hormone (GnRH). Previously, loss-of-function mutations in human MKRN3, encoding a putative E3 ubiquitin ligase, were found to contribute to about 30% of cases of familial CPP. MKRN3 was thereby suggested to serve as a 'brake' of mammalian puberty onset, but the underlying mechanisms remain as yet unknown. Here, we report that genetic ablation of Mkrn3 did accelerate mouse puberty onset with increased production of hypothalamic GnRH1. MKRN3 interacts with and ubiquitinates MBD3, which epigenetically silences GNRH1 through disrupting the MBD3 binding to the GNRH1 promoter and recruitment of DNA demethylase TET2. Our findings have thus delineated a molecular mechanism through which the MKRN3-MBD3 axis controls the epigenetic switch in the onset of mammalian puberty.

引用

页码：671 / 685

页数：15

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