Skip to main content
SpringerLink
Log in

The Interplay of Non-coding RNAs and X Chromosome Inactivation in Human Disease

  • Chapter
  • First Online:
Book cover Systems Biology

Part of the book series: RNA Technologies ((RNATECHN))

Abstract

Non-coding RNAs (ncRNAs) represent key molecular players in biological processes and human disease. Several ncRNA types have been discovered including microRNAs (miRNAs) of around 23 nucleotides and long non-coding RNAs (lncRNAs) that are above 200 nucleotides in length. One of the first functional ncRNAs discovered was the lncRNA named X inactive specific transcript (XIST). XIST is the main actor in a fundamental process called X chromosome inactivation (XCI) where, in females, one of the two X chromosomes is silenced to balance the extra gene expression dosage. In this book chapter, we present the emerging evidence for the importance of XCI in diseases such as gastric and bladder cancer and genetic pathologies such as Klinefelter (47,XXY) and Turner (45,X0) syndromes. Furthermore, a new role for the crosstalk between XIST and miRNAs is discussed. Finally, new evidence for sex bias of XCI in human tissues and development of cancer is presented.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Avner P, Heard E (2001) X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2:59–67

    Article  CAS  PubMed  Google Scholar 

  • Barr ML, Bertram EG (1949) A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163:676

    Article  CAS  PubMed  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Belling K, Russo F, Jensen AB et al (2017) Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity. Hum Mol Genet 26:1219–1229

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA et al (2017) Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest 40:123–134

    Article  CAS  PubMed  Google Scholar 

  • Brannan CI, Dees EC, Ingram RS, Tilghman SM (1990) The product of the H19 gene may function as an RNA. Mol Cell Biol 10:28–36

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brockdorff N, Ashworth A, Kay GF et al (1992) The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71:515–526

    Article  CAS  PubMed  Google Scholar 

  • Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y et al (1992) The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71:527–542

    Article  CAS  PubMed  Google Scholar 

  • Calin GA, Dumitru CD, Shimizu M et al (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Calin GA, Sevignani C, Dumitru CD et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101:2999–3004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Calin GA, Ferracin M, Cimmino A et al (2005) A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793–1801

    Article  CAS  PubMed  Google Scholar 

  • Cerase A, Pintacuda G, Tattermusch A, Avner P (2015) Xist localization and function: new insights from multiple levels. Genome Biol 16:166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chaligne R, Heard E (2014) X-chromosome inactivation in development and cancer. FEBS Lett 588:2514–2522

    Article  CAS  PubMed  Google Scholar 

  • Chen DL, Chen LZ, Lu YX et al (2017) Long noncoding RNA XIST expedites metastasis and modulates epithelial-mesenchymal transition in colorectal cancer. Cell Death Dis 8:e3011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cook MB, Dawsey SM, Freedman ND et al (2009) Sex disparities in cancer incidence by period and age. Cancer Epidemiol Biomark Prev 18:1174–1182

    Article  Google Scholar 

  • Dunford A, Weinstock DM, Savova V et al (2017) Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat Genet 49:10–16

    Article  CAS  PubMed  Google Scholar 

  • Ebert MS, Sharp PA (2010) Emerging roles for natural microRNA sponges. Curr Biol 20:R858–R861

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Edgren G, Liang L, Adami HO, Chang ET (2012) Enigmatic sex disparities in cancer incidence. Eur J Epidemiol 27:187–196

    Article  PubMed  Google Scholar 

  • Epstein CJ, Smith S, Travis B, Tucker G (1978) Both X chromosomes function before visible X-chromosome inactivation in female mouse embryos. Nature 274:500–503

    Article  CAS  PubMed  Google Scholar 

  • Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    Article  CAS  PubMed  Google Scholar 

  • Goto T, Monk M (1998) Regulation of X-chromosome inactivation in development in mice and humans. Microbiol Mol Biol Rev 62:362–378

    PubMed  PubMed Central  CAS  Google Scholar 

  • Hu JX, Thomas CE, Brunak S (2016) Network biology concepts in complex disease comorbidities. Nat Rev Genet 17:615–629

    Article  CAS  PubMed  Google Scholar 

  • Hwang HW, Wentzel EA, Mendell JT (2007) A hexanucleotide element directs microRNA nuclear import. Science 315:97–100

    Article  CAS  PubMed  Google Scholar 

  • Iorio MV, Ferracin M, Liu CG et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070

    Article  CAS  PubMed  Google Scholar 

  • Jensen AB, Moseley PL, Oprea TI et al (2014) Temporal disease trajectories condensed from population-wide registry data covering 6.2 million patients. Nat Commun 5:4022

    Article  CAS  PubMed  Google Scholar 

  • Jiang J, Jing Y, Cost GJ et al (2013) Translating dosage compensation to trisomy 21. Nature 500:296–300

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kay GF, Penny GD, Patel D, Ashworth A, Brockdorff N et al (1993) Expression of Xist during mouse development suggests a role in the initiation of X chromosome inactivation. Cell 72:171–182

    Article  CAS  PubMed  Google Scholar 

  • Kratzer PG, Gartler SM (1978) HGPRT activity changes in preimplantation mouse embryos. Nature 274:503–504

    Article  CAS  PubMed  Google Scholar 

  • Lagana A, Russo F, Sismeiro C, Giugno R, Pulvirenti A et al (2010) Variability in the incidence of miRNAs and genes in fragile sites and the role of repeats and CpG islands in the distribution of genetic material. PLoS One 5:e11166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee JT (2005) Regulation of X-chromosome counting by Tsix and Xite sequences. Science 309:768–771

    Article  CAS  PubMed  Google Scholar 

  • Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854

    Article  CAS  PubMed  Google Scholar 

  • Lu Q, Yu T, Ou X, Cao D, Xie T, Chen X (2017) Potential lncRNA diagnostic biomarkers for early gastric cancer. Mol Med Rep 16:9545–9552

    Article  CAS  PubMed  Google Scholar 

  • Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373

    Article  CAS  PubMed  Google Scholar 

  • Ma L, Zhou Y, Luo X, Gao H, Deng X et al (2017) Long non-coding RNA XIST promotes cell growth and invasion through regulating miR-497/MACC1 axis in gastric cancer. Oncotarget 8:4125–4135

    PubMed  Google Scholar 

  • Minkovsky A, Barakat TS, Sellami N, Chin MH, Gunhanlar N et al (2013) The pluripotency factor-bound intron 1 of Xist is dispensable for X chromosome inactivation and reactivation in vitro and in vivo. Cell Rep 3:905–918

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mo Y, Lu Y, Wang P et al (2017) Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma. Tumour Biol 39:1010428317690999

    Article  PubMed  Google Scholar 

  • Monk M, Harper M (1978) X-chromosome activity in preimplantation mouse embryos from XX and XO mothers. J Embryol Exp Morphol 46:53–64

    PubMed  CAS  Google Scholar 

  • Mueller JL, Skaletsky H, Brown LG et al (2013) Independent specialization of the human and mouse X chromosomes for the male germ line. Nat Genet 45:1083–1087

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Okamoto I, Arnaud D, Le Baccon P, Otte AP, Disteche CM et al (2005) Evidence for de novo imprinted X-chromosome inactivation independent of meiotic inactivation in mice. Nature 438:369–373

    Article  CAS  PubMed  Google Scholar 

  • Okita K, Yamanaka S (2011) Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond B Biol Sci 366:2198–2207

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Passerini V, Ozeri-Galai E, de Pagter MS et al (2016) The presence of extra chromosomes leads to genomic instability. Nat Commun 7:10754

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pfeffer SR, Yang CH, Pfeffer LM (2015) The role of miR-21 in cancer. Drug Dev Res 76:270–277

    Article  CAS  PubMed  Google Scholar 

  • Raudsepp T, Das PJ, Avila F, Chowdhary BP (2012) The pseudoautosomal region and sex chromosome aneuploidies in domestic species. Sex Dev 6:72–83

    Article  CAS  PubMed  Google Scholar 

  • Soh YQ, Alföldi J, Pyntikova T et al (2014) Sequencing the mouse Y chromosome reveals convergent gene acquisition and amplification on both sex chromosomes. Cell 159:800–813

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Song SJ, Poliseno L, Song MS et al (2013) MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154:311–324

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Takagi N, Wake N, Sasaki M (1978) Cytologic evidence for preferential inactivation of the paternally derived X chromosome in XX mouse blastocysts. Cytogenet Cell Genet 20:240–248

    Article  CAS  PubMed  Google Scholar 

  • Tantai J, Hu D, Yang Y, Geng J (2015) Combined identification of long non-coding RNA XIST and HIF1A-AS1 in serum as an effective screening for non-small cell lung cancer. Int J Clin Exp Pathol 8:7887–7895

    PubMed  PubMed Central  CAS  Google Scholar 

  • Theisen A, Shaffer LG (2010) Disorders caused by chromosome abnormalities. Appl Clin Genet 3:159–174

    PubMed  PubMed Central  CAS  Google Scholar 

  • Thompson SL, Bakhoum SF, Compton DA (2010) Mechanisms of chromosomal instability. Curr Biol 20:R285–R295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tukiainen T, Villani AC, Yen A et al (2017) Landscape of X chromosome inactivation across human tissues. Nature 550:244–248

    Article  PubMed Central  PubMed  Google Scholar 

  • Xiong Y, Wang L, Li Y, Chen M, He W et al (2017) The long non-coding RNA XIST interacted with MiR-124 to modulate bladder cancer growth, invasion and migration by targeting androgen receptor (AR). Cell Physiol Biochem 43:405–418

    Article  CAS  PubMed  Google Scholar 

  • Zhang B, Pan X, Cobb GP, Anderson TA (2007) MicroRNAs as oncogenes and tumor suppressors. Dev Biol 302:1–12

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Guo X, Tian T et al (2017) Detection of turner syndrome using X-chromosome inactivation specific differentially methylated CpG sites: a pilot study. Clin Chim Acta 468:174–179

    Article  CAS  PubMed  Google Scholar 

  • Zinn AR, Page DC, Fisher EM (1993) Turner syndrome: the case of the missing sex chromosome. Trends Genet 9:90–93

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the Novo Nordisk Foundation for supporting our research (grant agreement NNF14CC0001).

Author information

Authors and Affiliations

  1. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Francesco Russo, Søren Brunak & Kirstine Belling

  2. Intomics A/S, Lyngby (Copenhagen), Denmark

    Federico De Masi

Authors
  1. Francesco Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federico De Masi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Søren Brunak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kirstine Belling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Russo .

Editor information

Editors and Affiliations

  1. Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin-Buch, Berlin, Germany

    Nikolaus Rajewsky

  2. Nanobiomedical Center, Adam Mickiewicz University, Poznań, Poland

    Stefan Jurga

  3. Polish Academy of Sciences, Institute of Bioorganic Chemistry, Poznań, Poland

    Jan Barciszewski

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Russo, F., De Masi, F., Brunak, S., Belling, K. (2018). The Interplay of Non-coding RNAs and X Chromosome Inactivation in Human Disease. In: Rajewsky, N., Jurga, S., Barciszewski, J. (eds) Systems Biology. RNA Technologies. Springer, Cham. https://doi.org/10.1007/978-3-319-92967-5_11

Download citation

Publish with us

Policies and ethics

Search

Navigation