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MKRN3 Regulates the Epigenetic Switch of Mammalian Puberty Via National Science Review RESEARCH ARTICLE 7: 671–685, 2020 doi: 10.1093/nsr/nwaa023 1Department of Pediatrics, Advance access publication 14 February 2020 Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory MOLECULAR BIOLOGY & GENETICS of Molecular Biology, CAS Center for Excellence in Molecular Cell Institute of Biochemistry and Cell MKRN3 regulates the epigenetic switch of mammalian Biology, Chinese Academy of Sciences, Shanghai 200031, China; 2University of puberty via ubiquitination of MBD3 Chinese Academy of Sciences, Beijing 100049, 3 1,2,† 1,† 1,2,3,† 1,2 4 China; CAS Key Laboratory Chuanyin Li ,WenliLu , Liguang Yang , Zhengwei Li , Xiaoyi Zhou , of Computational Biology, Downloaded from https://academic.oup.com/nsr/article/7/3/671/5736025 by guest on 23 September 2021 CAS-MPG Partner Institute Rong Guo1,2, Junqi Wang1, Zhebao Wu5, Zhiya Dong1, Guang Ning6, Yujiang Shi7,8, for Computational Biology, Shanghai Institute of 9 1,2 1,2 1,2 1,2 Nutrition and Health, Yinmin Gu , Peng Chen , Zijian Hao , Tianting Han , Meiqiang Yang , Shanghai Institutes for 1 4 1,2,3,∗ 9,∗ 1,2,10,∗ Biological Sciences, Wei Wang , Xuehui Huang ,YixueLi , Shan Gao and Ronggui Hu University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, ABSTRACT China; 4College of Life Sciences, Shanghai Normal Central precocious puberty (CPP) refers to a human syndrome of early puberty initiation with University, Shanghai 200234, characteristic increase in hypothalamic production and release of gonadotropin-releasing hormone China; 5Center for Pituitary Tumor, Ruijin Hospital (GnRH). Previously, loss-of-function mutations in human MKRN3, encoding a putative E3 ubiquitin Affiliated to Shanghai Jiao ligase, were found to contribute to about 30% of cases of familial CPP. MKRN3 was thereby suggested to Tong University, Shanghai 200025, China; 6Shanghai serve as a ‘brake’ of mammalian puberty onset, but the underlying mechanisms remain as yet unknown. Institute of Endocrine and Here, we report that genetic ablation of Mkrn3 did accelerate mouse puberty onset with increased Metabolic Diseases, Shanghai Key Laboratory for production of hypothalamic GnRH1. MKRN3 interacts with and ubiquitinates MBD3, which Endocrine Tumors and epigenetically silences GNRH1 through disrupting the MBD3 binding to the GNRH1 promoter and E-Institute for Endocrinology, Ruijin Hospital, Shanghai recruitment of DNA demethylase TET2. Our findings have thus delineated a molecular mechanism Jiao Tong University School through which the MKRN3–MBD3 axis controls the epigenetic switch in the onset of mammalian puberty. of Medicine, Shanghai 200025, China; 7Division of Keywords: Endocrinology, Diabetes and ubiquitin, MKRN3, DNA methylation, MBD3, DNA demethylase, central precocious puberty Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, INTRODUCTION that clinically defines those who develop secondary MA 02115, USA; 8Harvard Medical School, Boston, MA sexual characteristics before the age of 8 years in 02115, USA; 9CAS Key Mammalian puberty is a process through which sex- girls or 9 years in boys. CPP is currently esti- Laboratory of Bio-medical ual competence and reproduction are attained un- Diagnostics, Suzhou Institute mated to affect approximately 1 in 5000–10 000 of Biomedical Engineering der the regulation of the anatomic hypothalamic– of the population worldwide, resulting from com- and Technology, Chinese pituitary–gonadal (HPG) axis [1]. The HPG axis is plex interactions among genetic, nutritional, en- Academy of Sciences, Suzhou 215163, China and active during fetal and neonatal stages, but becomes vironmental and socioeconomic factors. The dys- 10Cancer Center, Shanghai quiescent during childhood, until ultimately reacti- regulated timing of puberty is known to associate Tenth People’s Hospital, School of Medicine, Tongji vated upon pubertal initiation, which is character- with risks of many subsequent diseases, e.g. ear- University, Shanghai ized by an increase in the amplitude and frequency of lier age of menarche in girls is associated with in- 200072, China pulsatile hypothalamic gonadotropin-releasing hor- creased risks of breast cancer, endometrial can- mone (GnRH) release. The re-emergence of pul- ∗Corresponding authors. cer, obesity, type 2 diabetes and cardiovascular dis- E-mails: [email protected]; satile GnRH secretion subsequently leads to in- ease, indicating the critical importance of the del- [email protected]; creases in the secretion of gonadotropins, luteiniz- icate but as-yet-unknown mechanisms that regu- [email protected] †Equally contributed to this ing hormone (LH) and follicle-stimulating hor- late human puberty [3,4]. Meanwhile, epigenetic work. mone (FSH) by the anterior pituitary gland and reprogramming has been proposed to play pivotal the consequent activation of gonadal function [2]. roles in the expression of puberty-related genes Received 18 November The HPG axis can also be prematurely activated 2019; Revised 10 January in the control of puberty initiation and develop- 2020; Accepted 13 to initiate gonadotropin-dependent precocious pu- ment, with detailed mechanisms as yet incompletely February 2020 berty, resulting in central precocious puberty (CPP) understood [5–7]. C The Author(s) 2020. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. This is an Open Access articleder distributedun the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 672 Natl Sci Rev, 2020, Vol. 7, No. 3 RESEARCH ARTICLE A recent study has revealed mutations or dele- entially modulate the homeostasis and function of tions in the human MKRN3 (Makorin ring fin- MBD3 in a spatiotemporally controlled manner. ger protein 3) gene in familial CPP cohorts, which However, it remains entirely unknown whether was estimated to contribute to ∼30% of familial and how such post-translational modifications CPP cases worldwide [8]. As many of these muta- might occur and regulate MBD3 function in any tions might disrupt the MKRN3 structure and im- pathophysiologically meaningful way. pair its E3 ubiquitin ligase activity, MKRN3 was In this work, we generated the first genetic model proposed to act as a ‘brake’ or repressor of GnRH of human CPP by constructing a Mkrn3 knockout production in regulating mammalian puberty. How- mouse strain and establishing its role in regulating ever, it remains totally unclear how the disease- the onset of puberty and a repressor role in regulat- causing mutations or deletions in the MKRN3 ing Gnrh1 expression. We next identified MBD3 as gene lead to premature GnRH production and a novel physiological substrate for the E3 ubiquitin Downloaded from https://academic.oup.com/nsr/article/7/3/671/5736025 by guest on 23 September 2021 release [9]. ligase activity of MKRN3. MKRN3-mediated ubiq- DNA methylation and demethylation are catal- uitination was found to disrupt the interactions be- ysed by DNA methyltransferases (DNMTs) and tween MBD3 with 5hmC-containing GNRH1 pro- demethylases (human ten-eleven translocation moter or TET2, resulting in the epigenetic silence of methylcytosine dioxygenases, TETs), respectively. GNRH1 expression. Moreover, it was confirmed in Such reactions occur at the carbon-5 position of patient-derived cells that the disease-causing muta- cytosine residues in CpG nucleotides, leading to the tions indeed impaired the ubiquitination of endoge- formation or decomposition of 5-methylcytosine nous MBD3, supporting a strong clinical relevance (5mC), 5-hydroxylmethylcytosine (5hmC) and of our experimental findings. other derivatives, which constitutes a fundamental epigenetic mechanism that regulates gene expres- sion in mammalian cells [10–13]. Proteins of the RESULTS methyl-CpG-binding domain (MBD) family were Maternally imprinted Mkrn3 regulates first defined as those that read DNA methylation the onset of puberty and represses Gnrh1 and recruit chromatin remodelers, e.g. histone deacetylases and methyltransferases, to methylated expression in mice DNA and repress gene expression [14]. Among The mouse Mkrn3 gene contains a single exon MBDs (Methyl-CpG-DNA binding proteins), and resides adjacent to the Prader–Willi Syndrome MBD2 and MBD3 interact with the nucleosome Imprinting Center (PWS-IC) on chromosome 7, remodeling deacetylase (NuRD/Mi-2) complex which encodes Mkrn3 protein that shares high se- members to repress gene expression. However, quence homology with other mammalian orthologs unlike MBD2 that binds to methylated DNAs and (Fig. 1A and Supplementary Fig. 1A). The mouse mainly represses gene expression, MBD3 has been Mkrn3 gene was expressed in tissues with a dis- shown to bind primarily to promoters, exons and tinct pattern, being most abundant throughout the enhancers of actively transcribed genes, suggesting brain, lower in testis and barely detectible in all more diverse roles of MBD3 in regulating gene ex- other tissues examined (Supplementary Fig. 1B). pression [15–18]. MBD3 and some of its isoforms Mkrn3 protein expression in mouse hypothalamus were found to interact with and promote the DNA was found to undergo an age-dependent decrease demethylase activity of human ten-eleven translo- during development, with a sharp reduction occur- cation methylcytosine dioxygenase 2 (TET2), ringatpostnatalday15today18,coincidingwiththe
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