Skip to main content
Log in

XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a

Human Genetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • McLaren A (1991) Sex determination in mammals. Oxf Rev Reprod Biol 13:1–33

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Resnick JL, Bixler LS, Cheng L, Donovan PJ (1992) Long-term proliferation of mouse primordial germ cells in culture. Nature 359:550–551

    Article  CAS  PubMed  Google Scholar 

  • Richards JS, Pangas SA (2010) The ovary: basic biology and clinical implications. J Clin Invest 120:963–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su JL, Chen PS, Johansson G, Kuo ML (2012) Function and regulation of let-7 family microRNAs. Microrna 1:34–39

    Article  CAS  PubMed  Google Scholar 

  • Sybert VP, McCauley E (2004) Turner’s syndrome. N Engl J Med 351:1227–1238

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zinn AR, Ross JL (1998) Turner syndrome and haploinsufficiency. Curr Opin Genet Dev 8:322–327

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors

Corresponding author

Correspondence to He-Feng Huang.

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-016-1752-9

Keywords

Navigation