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

Chuanyin Li; Wenli Lu; Liguang Yang; Zhengwei Li; Xiaoyi Zhou; Rong Guo; Junqi Wang; Zhebao Wu; Zhiya Dong; Guang Ning; Yujiang Shi; Yinmin Gu; Peng Chen; Zijian Hao; Tianting Han; Meiqiang Yang; Wei Wang; Xuehui Huang; Yixue Li; Shan Gao; Ronggui Hu

doi:10.1093/nsr/nwaa023

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

Natl Sci Rev. 2020 Mar;7(3):671-685. doi: 10.1093/nsr/nwaa023. Epub 2020 Feb 14.

Authors

Chuanyin Li^{1

2}, Wenli Lu¹, Liguang Yang^{1

2

3}, Zhengwei Li^{1

2}, Xiaoyi Zhou⁴, Rong Guo^{1

2}, Junqi Wang¹, Zhebao Wu⁵, Zhiya Dong¹, Guang Ning⁶, Yujiang Shi^{7

8}, Yinmin Gu⁹, Peng Chen^{1

2}, Zijian Hao^{1

2}, Tianting Han^{1

2}, Meiqiang Yang^{1

2}, Wei Wang¹, Xuehui Huang⁴, Yixue Li^{1

2

3}, Shan Gao⁹, Ronggui Hu^{1

2

10}

Affiliations

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

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.

Keywords: DNA demethylase; DNA methylation; MBD3; MKRN3; central precocious puberty; ubiquitin.