MeCP2 duplication causes hyperandrogenism by upregulating LHCGR and downregulating RORα

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 inc...

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Bibliographic Details
Published in:Cell death & disease 2021-10, Vol.12 (11), p.999-999, Article 999
Main Authors: Wang, Yu-Meng, Wu, Yu, Zheng, Yu-Fang, Wang, Hong-Yan
Format: Article
Language:English
Subjects:
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Androgens
Animals
Antibodies
Aromatase
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
CpG islands
Developmental disabilities
Disease Models, Animal
Down-Regulation
Humans
Hyperandrogenism - genetics
Hyperandrogenism - physiopathology
Immunology
Leydig cells
Life Sciences
Luteinizing hormone
Male
MeCP2 protein
Methyl-CpG binding protein
Methyl-CpG-Binding Protein 2 - metabolism
Mice
Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism
Puberty
Receptors, LH - metabolism
Sex hormones
Transcription
Up-Regulation
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-021-04277-4