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

Author:

Li Chuanyin12,Lu Wenli1,Yang Liguang123,Li Zhengwei12,Zhou Xiaoyi4,Guo Rong12,Wang Junqi1,Wu Zhebao5,Dong Zhiya1,Ning Guang6,Shi Yujiang78,Gu Yinmin9,Chen Peng12,Hao Zijian12,Han Tianting12,Yang Meiqiang12,Wang Wei1,Huang Xuehui4,Li Yixue123,Gao Shan9,Hu Ronggui1210ORCID

Affiliation:

1. Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China

2. University of Chinese Academy of Sciences, Beijing 100049, China

3. CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China

4. College of Life Sciences, Shanghai Normal University, Shanghai 200234, China

5. Center for Pituitary Tumor, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200025, China

6. Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors and E-Institute for Endocrinology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

7. Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA

8. Harvard Medical School, Boston, MA 02115, USA

9. CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China

10. Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China

Abstract

Abstract 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.

Funder

Chinese Academy of Sciences

National Natural Science Foundation of China

model animal project of Shanghai Science and Technology Commission

Ministry of Science and Technology of China

China Postdoctoral Science Foundation

Shanghai Municipal Science and Technology Major Project

Publisher

Oxford University Press (OUP)

Subject

Multidisciplinary

Cited by 48 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3