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.
Highlights
As an epigenetic regulator, the DNA binding protein methyl-CpGbinding protein 2 (MeCP2) is known for its important neurology and brain function
Elevated androgen in MeCP2Tg1 mice To evaluate the correlation of elevated MeCP2 and sex hormones level in MeCP2Tg1 mice, the concentrations of serum testosterone were detected by ELISA in MeCP2Tg1 male mice or wild-type (WT) littermates males at 3-week-old, 7-week-old, 1Obstetrics and Gynaecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China. 2Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai 200433, China. 3Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China. ✉email: zhengyf@fudan.edu.cn; wanghylab@fudan.edu.cn Edited by Dr Yufang Shi
The duplication-induced androgen elevation is not affected by hypothalamic-pituitary axis (HPA). luciferase activities of TM3 cells transfected with Lhcgr-WT, Lhcgr-In order to evaluate the potential effect of duplicated MeCP2 on ΔCGI-I, or Lhcgr-ΔCGI-II were significantly upregulated when coandrogen synthesis, we investigated whether MeCP2 is transfected with MeCP2, while that of Lhcgr-dΔCGI co-transfection expressed in testis
Summary
The DNA binding protein methyl-CpGbinding protein 2 (MeCP2) is known for its important neurology and brain function. Loss and gain of function of MeCP2 lead to Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively, which are two severe neurological disorders characterized by intellectual disability, autism, and developmental regression [1, 2]. The functional studies of MeCP2 have been largely focused on its role in brain development [3]. Recent studies have shown that precocious puberty with hyperandrogenism is another clinical feature of patients with MDS and MeCP2 mutations [8,9,10], suggesting that MeCP2 may play an important role in androgen synthesis. Whether or how MeCP2 plays a role in the process of sex hormone synthesis is unclear
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