title: XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a.
abstract: Mechanisms underlying female gonadal dysgenesis remain unclarified and relatively unstudied. Whether X-chromosome inactivation (XCI)-escaping genes and microRNAs (miRNAs) contribute to this condition is currently unknown. We compared 45,X Turner Syndrome women with 46,XX normal women, and investigated differentially expressed miRNAs in Turner Syndrome through plasma miRNA sequencing. We found that miR-320a was consistently upregulated not only in 45,X plasma and peripheral blood mononuclear cells (PBMCs), but also in 45,X fetal gonadal tissues. The levels of miR-320a in PBMCs from 45,X, 46,XX, 46,XY, and 47,XXY human subjects were inversely related to the expression levels of XCI-escaping gene KDM5C in PBMCs. In vitro models indicated that KDM5C suppressed miR-320a transcription by directly binding to the promoter of miR-320a to prevent histone methylation. In addition, we demonstrated that KITLG, an essential gene for ovarian development and primordial germ cell survival, was a direct target of miR-320a and that it was downregulated in 45,X fetal gonadal tissues. In conclusion, we demonstrated that downregulation of miR-320a by the XCI-escaping gene KDM5C contributed to ovarian development by targeting KITLG.
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Yi-Xi
authors.initials: YX
authors.lastname: Sun
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Xu
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Song-Chang
authors.initials: SC
authors.lastname: Chen
authors.affiliation: International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.|Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education (Shanghai Jiao Tong University), Shanghai, 200030, China.
authors.forename: Jun-Yu
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ye-Chun
authors.initials: YC
authors.lastname: Ruan
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Run-Ju
authors.initials: RJ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Ye-Qing
authors.initials: YQ
authors.lastname: Qian
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Liu
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China.
authors.forename: Lu-Yang
authors.initials: LY
authors.lastname: Jin
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Yu
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Xu
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
authors.forename: Yu-Qin
authors.initials: YQ
authors.lastname: Luo
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Xin-Mei
authors.initials: XM
authors.lastname: Liu
authors.affiliation: International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.|Institute of Embryo-Fetal Original Adult Disease and Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China.|Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Sheng
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, Zhejiang, China. huanghefg@hotmail.com.|International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China. huanghefg@hotmail.com.|Institute of Embryo-Fetal Original Adult Disease and Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China. huanghefg@hotmail.com.|Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education (Shanghai Jiao Tong University), Shanghai, 200030, China. huanghefg@hotmail.com.|Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310006, Zhejiang, China. huanghefg@hotmail.com.
authors.forename: He-Feng
authors.initials: HF
authors.lastname: Huang
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D063990:Gene Ontology; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D010053:Ovary / Q000254:growth & development*; D011401:Promoter Regions, Genetic; D017423:Sequence Analysis, RNA; D014424:Turner Syndrome / Q000235:genetics*; D015854:Up-Regulation; D049951:X Chromosome Inactivation / Q000235:genetics*; D055815:Young Adult
chemical_list: C572916:MIRN320 microRNA, human; C560945:MIRN486 microRNA, human; D035683:MicroRNAs; D056466:Histone Demethylases; C086877:KDM5C protein, human