1. Academic Validation
  2. MeCP2 duplication causes hyperandrogenism by upregulating LHCGR and downregulating RORα

MeCP2 duplication causes hyperandrogenism by upregulating LHCGR and downregulating RORα

  • Cell Death Dis. 2021 Oct 25;12(11):999. doi: 10.1038/s41419-021-04277-4.
Yu-Meng Wang 1 2 Yu Wu 2 Yu-Fang Zheng 3 4 Hong-Yan Wang 5 6
Affiliations

Affiliations

  • 1 Obstetrics and Gynaecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China.
  • 2 Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai, 200433, China.
  • 3 Obstetrics and Gynaecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China. zhengyf@fudan.edu.cn.
  • 4 Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai, 200433, China. zhengyf@fudan.edu.cn.
  • 5 Obstetrics and Gynaecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China. wanghylab@fudan.edu.cn.
  • 6 Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China. wanghylab@fudan.edu.cn.
Abstract

Duplication of MECP2 (methyl-CpG-binding protein 2) gene causes a serious neurological and developmental disorder called MECP2 duplication syndrome (MDS), which is usually found in males. A previous clinical study reported that MDS patient has precocious puberty with hyperandrogenism, suggesting increased MeCP2 may cause male hyperandrogenism. Here we use an MDS mouse model and confirm that MECP2 duplication significantly upregulates androgen levels. We show for the first time that MeCP2 is highly expressed in the Leydig cells of testis, where androgen is synthesized. Mechanistically, MECP2 duplication increases androgen synthesis and decreases androgen to estrogen conversion through either the upregulation of luteinizing hormone receptor (LHCGR) in testis, as a result of MeCP2 binds to G-quadruplex structure of Lhcgr promoter and recruits the transcription activator CREB1 or the downregulation of the expression of aromatase in testis by binding the CpG island of RORα, an upstream regulator of aromatase. Taken together, we demonstrate that MeCP2 plays an important role in androgen synthesis, supporting a novel non-CNS function of MeCP2 in the process of sex hormone synthesis.

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