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.
Abbreviations
- miRNA:
-
microRNA
- TS:
-
Turner syndrome
- PBMCs:
-
Peripheral blood mononuclear cells
- XCI:
-
X-chromosome inactivation
- H3K4me3:
-
H3-tri-methylated K4
References
Berletch JB, Yang F, Xu J, Carrel L, Disteche CM (2011) Genes that escape from X inactivation. Hum Genet 130:237–245
Calabrese JM, Sun W, Song L, Mugford JW, Williams L, Yee D, Starmer J, Mieczkowski P, Crawford GE, Magnuson T (2012) Site-specific silencing of regulatory elements as a mechanism of X inactivation. Cell 151:951–963
Castronovo C, Rossetti R, Rusconi D, Recalcati MP, Cacciatore C, Beccaria E, Calcaterra V, Invernizzi P, Larizza D, Finelli P, Persani L (2014) Gene dosage as a relevant mechanism contributing to the determination of ovarian function in Turner syndrome. Hum Reprod 29:368–379
Childs AJ, Kinnell HL, Collins CS, Hogg K, Bayne RA, Green SJ, McNeilly AS, Anderson RA (2010) BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis. Stem Cells 28:1368–1378
Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA (2011) MicroRNAs in body fluids—the mix of hormones and biomarkers. Nat Rev Clin Oncol 8:467–477
Dolci S, Williams DE, Ernst MK, Resnick JL, Brannan CI, Lock LF, Lyman SD, Boswell HS, Donovan PJ (1991) Requirement for mast cell growth factor for primordial germ cell survival in culture. Nature 352:809–811
Dudley BM, Runyan C, Takeuchi Y, Schaible K, Molyneaux K (2007) BMP signaling regulates PGC numbers and motility in organ culture. Mech Dev 124:68–77
Feng R, Sang Q, Zhu Y, Fu W, Liu M, Xu Y, Shi H, Xu Y, Qu R, Chai R, Shao R, Jin L, He L, Sun X, Wang L (2015) MiRNA-320 in the human follicular fluid is associated with embryo quality in vivo and affects mouse embryonic development in vitro. Sci Rep 5:8689
Fisher EM, Beer-Romero P, Brown LG, Ridley A, McNeil JA, Lawrence JB, Willard HF, Bieber FR, Page DC (1990) Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell 63:1205–1218
Guan X, Gao Y, Zhou J, Wang J, Zheng F, Guo F, Chang A, Li X, Wang B (2015) miR-223 regulates adipogenic and osteogenic differentiation of mesenchymal stem cells through a C/EBPs/miR-223/FGFR2 regulatory feedback loop. Stem Cells
Guo X, Su B, Zhou Z, Sha J (2009) Rapid evolution of mammalian X-linked testis microRNAs. BMC Genom 10:97
Hamam D, Ali D, Vishnubalaji R, Hamam R, Al-Nbaheen M, Chen L, Kassem M, Aldahmash A, Alajez NM (2014) microRNA-320/RUNX2 axis regulates adipocytic differentiation of human mesenchymal (skeletal) stem cells. Cell Death Dis 5:e1499
He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531
Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y (2007) The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128:1077–1088
Jia CY, Li HH, Zhu XC, Dong YW, Fu D, Zhao QL, Wu W, Wu XZ (2011) MiR-223 suppresses cell proliferation by targeting IGF-1R. PLoS One 6:e27008
Jin X, Han CS, Yu FQ, Wei P, Hu ZY, Liu YX (2005) Anti-apoptotic action of stem cell factor on oocytes in primordial follicles and its signal transduction. Mol Reprod Dev 70:82–90
Johnston CM, Lovell FL, Leongamornlert DA, Stranger BE, Dermitzakis ET, Ross MT (2008) Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. PLoS Genet 4:e9
Lee JT (2011) Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control. Nat Rev Mol Cell Biol 12:815–826
McLaren A (1991) Sex determination in mammals. Oxf Rev Reprod Biol 13:1–33
Outchkourov NS, Muino JM, Kaufmann K, van Ijcken WF, Groot KM, van Leenen D, de Graaf P, Holstege FC, Grosveld FG, Timmers HT (2013) Balancing of histone H3K4 methylation states by the Kdm5c/SMCX histone demethylase modulates promoter and enhancer function. Cell Rep 3:1071–1079
Pesce M, Farrace MG, Piacentini M, Dolci S, De Felici M (1993) Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis). Development 118:1089–1094
Pierre A, Pisselet C, Dupont J, Bontoux M, Monget P (2005) Bone morphogenetic protein 5 expression in the rat ovary: biological effects on granulosa cell proliferation and steroidogenesis. Biol Reprod 73:1102–1108
Poulain M, Frydman N, Duquenne C, N’Tumba-Byn T, Benachi A, Habert R, Rouiller-Fabre V, Livera G (2012) Dexamethasone induces germ cell apoptosis in the human fetal ovary. J Clin Endocrinol Metab 97:E1890–E1897
Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du C, Tang W, Hamalainen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi I, Liu K (2008) Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 319:611–613
Resnick JL, Bixler LS, Cheng L, Donovan PJ (1992) Long-term proliferation of mouse primordial germ cells in culture. Nature 359:550–551
Richards JS, Pangas SA (2010) The ovary: basic biology and clinical implications. J Clin Invest 120:963–972
Sakata S, Sakamaki K, Watanabe K, Nakamura N, Toyokuni S, Nishimune Y, Mori C, Yonehara S (2003) Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice. Cell Death Differ 10:676–686
Sharp AJ, Stathaki E, Migliavacca E, Brahmachary M, Montgomery SB, Dupre Y, Antonarakis SE (2011) DNA methylation profiles of human active and inactive X chromosomes. Genome Res 21:1592–1600
Small EM, O’Rourke JR, Moresi V, Sutherland LB, McAnally J, Gerard RD, Richardson JA, Olson EN (2010) Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc Natl Acad Sci USA 107:4218–4223
Song R, Ro S, Michaels JD, Park C, McCarrey JR, Yan W (2009) Many X-linked microRNAs escape meiotic sex chromosome inactivation. Nat Genet 41:488–493
Su JL, Chen PS, Johansson G, Kuo ML (2012) Function and regulation of let-7 family microRNAs. Microrna 1:34–39
Sybert VP, McCauley E (2004) Turner’s syndrome. N Engl J Med 351:1227–1238
Tahiliani M, Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, Li J, Rao A, Shi Y (2007) The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature 447:601–605
Yi L, Hao Z, Yang T, Wang S, Xing B, Xu Y (2007) cDNA cloning, bioinformatic and tissue-specific expression analysis of porcine JARID1C gene. J Genet Genomics 34:1088–1096
Yin M, Wang X, Yao G, Lu M, Liang M, Sun Y, Sun F (2014) Transactivation of micrornA-320 by microRNA-383 regulates granulosa cell functions by targeting E2F1 and SF-1 proteins. J Biol Chem 289:18239–18257
Zinn AR, Ross JL (1998) Turner syndrome and haploinsufficiency. Curr Opin Genet Dev 8:322–327
Acknowledgements
This work is supported by the National Basic Research Program of China (No. 2013CB967404 to H. F. H), the National Natural Science Foundation of China (No. 81490742 and 31471405 to H. F. H, No. 81401219 to J. Y. Z.), the NSFC-CIHR Joint Health Research Program (No. 8161101434 to H. F. H., No. 81361128007 to J. Z. S.), the Shanghai Municipal Commission of Science and Technology Program (No. 14DJ1400100 to H. F. H., No. 15411966700 to J. Y. Z.), and the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1184 to H. F. H). We thank LetPub (http://www.letpub.com) for its linguistic assistance during the preparation of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflictof interest
The authors have declared no conflicts of interest.
Additional information
Y.-X. Sun, Y.-X. Zhang, and D. Zhang contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sun, YX., Zhang, YX., Zhang, D. et al. XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a. Hum Genet 136, 227–239 (2017). https://doi.org/10.1007/s00439-016-1752-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-016-1752-9