ABB  Vol.5 No.6 , May 2014
Revisiting the X-Chromosome Inactivation and Its Impact on Female Longevity
Abstract: X-chromosome inactivation is the genetic mechanism by which X-linked gene expression is equalized between the male and female genders of all placental mammal species. Given that the probability of mutant X-linked allele expression decreases as a result of the inactivation, it has been proposed that females have biological advantages relative to males. These advantages have grabbed the attention of the scientific community in recent years and have focused it on this topic and its clinical implications. To shed some new light on this intriguing phenomenon, this article reviews the most relevant molecular events involved in this process. These events include the role of Xist, the selection mechanism for future X-chromosome inactivation, the age-related inactivation skewing, and the relationship between inactivation and the emergence of X-linked diseases, possible treatments, and longevity.
Cite this paper: Chuaire-Noack, L. , Sánchez-Corredor, M. and Martínez-Agüero, M. (2014) Revisiting the X-Chromosome Inactivation and Its Impact on Female Longevity. Advances in Bioscience and Biotechnology, 5, 572-583. doi: 10.4236/abb.2014.56067.

[1]   vB Hjelmborg, J., Iachine, I., Skytthe, A., Vaupel, J.W., McGue, M., Koskenvuo, M., et al. (2006) Genetic Influence on Human Lifespan and Longevity. Human Genetics, 119, 312-321.

[2]   Kenyon, C. (2005) The Plasticity of Aging: Insights from Long-Lived Mutants. Cell, 120, 449-460.

[3]   Christensen, K., Johnson, T.E. and Vaupel, J.W. (2006) The Quest for Genetic Determinants of Human Longevity: Challenges and Insights. Nature Reviews Genetics, 7, 436-448.

[4]   United Nations, Department of Economic and Social Affairs/Population Division (2012) World Mortality Report 2011.

[5]   Lyon, M.F. (1961) Gene Action in the X-Chromosome of the Mouse (Musmusculus L.). Nature, 190, 372-373.

[6]   Austad, S.N. (2006) Why Women Live Longer than Men: Sex Differences in Longevity. Gender Medicine, 3, 79-92.

[7]   Migeon, B.R. (2007) Why Females Are Mosaics, X-Chromosome Inactivation, and Sex Differences in Disease. Gender Medicine, 4, 97-105.

[8]   Seifarth, J.E., McGowan, C.L. and Milne, K.J. (2012) Sex and Life Expectancy. Gender Medicine, 9, 390-401.

[9]   Graves, J.A. and Gartler, S.M. (1986) Mammalian X Chromosome Inactivation Testing the Hypothesis of Transcriptional Control. Somatic Cell and Molecular Genetics, 12, 275-280.

[10]   Christensen, K., Ørstavik, K.H. and Vaupel, J.W. (2001) The X Chromosome and the Female Survival Advantage. Annals of the New York Academy of Sciences, 954, 175-183.

[11]   van den Berg, I.M., Laven, J.S., Stevens, M., Jonkers, I., Galjaard, R.J., Gribnau, J., et al. (2009) X Chromosome Inactivation Is Initiated in Human Preimplantation Embryos. The American Journal of Human Genetics, 84, 771-779.

[12]   Spolarics, Z. (2007) The X-Files of Inflammation: Cellular Mosaicism of X-Linked Polymorphic Genes and the Female Advantage in the Host Response to Injury and Infection. Shock, 27, 597-604.

[13]   Tower, J. and Arbeitman, M. (2009) The Genetics of Gender and Life Span. Journal of Biology, 8, 38.

[14]   MapViewer Annotation Release 104.

[15]   Shevchenko, A.I., Zakharova, I.S. and Zakian, S.M. (2013) The Evolutionary Pathway of X Chromosome Inactivation in Mammals. ActaNaturae, 5, 40-53.

[16]   Lengner, C.J., Gimelbrant, A.A., Erwin, J.A., Cheng, A.W., Guenther, M.G., Welstead, G.G., et al. (2010) Derivation of Pre-X Inactivation Human Embryonic Stem Cells under Physiological Oxygen Concentrations. Cell, 141, 872-883.

[17]   Penny, G.D., Kay, G.F., Sheardown, S.A., Rastan, S. and Brockdorff, N. (1996) Requirement for Xist in X Chromosome Inactivation. Nature, 379, 131-137.

[18]   Zhao, J., Sun, B.K., Erwin, J.A., Song, J.J. and Lee, J.T. (2008) Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome. Science, 322, 750-756.

[19]   Jeon, Y., Sarma, K. and Lee, J.T. (2012) New and Xisting Regulatory Mechanisms of X Chromosome Inactivation. Current Opinion in Genetics & Development, 22, 62-71.

[20]   Wutz, A., Rasmussen, T.P. and Jaenisch, R. (2002) Chromosomal Silencing and Localization Are Mediated by Different Domains of Xist RNA. Nature Genetics, 30, 167-174.

[21]   Rastan, S. and Robertson, E.J. (1985) X-Chromosome Deletions in Embryo-Derived (EK) Cell Lines Associated with Lack of X-Chromosome Inactivation. Journal of Embryology and Experimental Morphology, 90, 379-388.

[22]   Lee, J.T. and Lu, N. (1999) Targeted Mutagenesis of Tsix Leads to Nonrandom X Inactivation. Cell, 99, 47-57.

[23]   Johnston, C.M., Newall, A.E., Brockdorff, N. and Nesterova, T.B. (2002) Enox, a Novel Gene that Maps 10 kb Upstream of Xist and Partially Escapes X Inactivation. Genomics, 80, 236-244.

[24]   Chureau, C., Prissette, M., Bourdet, A., Barbe, V., Cattolico, L., Jones, L., Eggen, A., Avner, P. and Duret, L. (2002) Comparative Sequence Analysis of the X-Inactivation Center Region in Mouse, Human, and Bovine. Genome Research, 12, 894-908.

[25]   Huynh, K.D. and Lee, J.T. (2003) Inheritance of a Pre-Inactivated Paternal X Chromosome in Early Mouse Embryos. Nature, 426, 857-862.

[26]   Okamoto, I., Otte, A.P., Allis, C.D., Reinberg, D. and Heard, E. (2004) Epigenetic Dynamics of Imprinted X Inactivation during Early Mouse Development. Science, 303, 644-649.

[27]   Patrat, C., Okamoto, I., Diabangouaya, P., Vialon, V., Le Baccon, P., Chow, J. and Heard, E. (2009) Dynamic Changes in Paternal X-Chromosome Activity during Imprinted X-Chromosome Inactivation in Mice. Proceedings of the National Academy of Sciences of the United States of America, 106, 5198-5203.

[28]   Navarro, P., Oldfield, A., Legoupi, J., Festuccia, N., Dubois, A., Attia, M., Schoorlemmer, J., Rougeulle, C., Chambers, I. and Avner, P. (2010) Molecular Coupling of Tsix Regulation and Pluripotency. Nature, 468, 457-460.

[29]   Ogawa, Y., Sun, B.K. and Lee, J.T. (2008) Intersection of the RNA Interference and X-Inactivation Pathways. Science, 320, 1336-1341.

[30]   Okamoto, I., Patrat, C., Thépot, D., Peynot, N., Fauque, P., Daniel, N., Diabangouaya, P., Wolf, J.P., Renard, J.P., Duranthon, V. and Heard, E. (2011) Eutherian Mammals Use Diverse Strategies to Initiate X-Chromosome Inactivation during Development. Nature, 472, 370-374.

[31]   van den Berg, I.M., Galjaard, R.J., Laven, J.S. and van Doorninck, J.H. (2011) XCI in Preimplantation Mouse and Human Embryos: First There Is Remodeling. Human Genetics, 130, 203-215.

[32]   Dvash, T., Lavon, N. and Fan, G.P. (2010) Variations of X Chromosome Inactivation Occur in Early Passages of Female Human Embryonic Stem Cells. PLoS One, 5, e11330.

[33]   Jeon, Y. and Lee, J.T. (2011) YY1 Tethers Xist RNA to the Inactive X Nucleation Center. Cell, 146, 119-133.

[34]   Escamilla-Del-Arenal, M., da Rocha, S.T. and Heard, E. (2011) Evolutionary Diversity and Developmental Regulation of X-Chromosome Inactivation. Human Genetics, 130, 307-327.

[35]   Chow, J.C., Ciaudo, C., Fazzari, M.J., Mise, N., Servant, N., Glass, J.L., et al. (2010) LINE-1 Activity in Facultative Heterochromatin Formation during X Chromosome Inactivation. Cell, 141, 956-969.

[36]   Heard, E., Rougeulle, C., Arnaud, D., Avner, P., Allis, C.D. and Spector, D.L. (2001) Methylation of Histone H3 at Lys-9 Is an Early Mark on the X Chromosome during X Inactivation. Cell, 107, 727-738.

[37]   Kohlmaier, A., Savarese, F., Lachner, M., Martens, J., Jenuwein, T. and Wutz, A. (2004) A Chromosomal Memory Triggered by Xist Regulates Histone Methylation in X Inactivation. PLoS Biology, 2, e171.

[38]   Ohhata, T. and Wutz, A. (2013) Reactivation of the Inactive X Chromosome in Development and Reprogramming. Cellular and Molecular Life Sciences, 70, 2443-2461.

[39]   Mermoud, J.E., Popova, B., Peters, A.H., Jenuwein, T. and Brockdorff, N. (2002) Histone H3 Lysine 9 Methylation Occurs Rapidly at the Onset of Random X Chromosome Inactivation. Current Biology, 12, 247-251.

[40]   Plath, K., Fang, J., Mlynarczyk-Evans, S.K., Cao, R., Worringer, K.A., Wang, H.B., de la Cruz, C.C., Otte, A.P., Panning, B. and Zhang, Y. (2003) Role of Histone H3 Lysine 27 Methylation in X Inactivation. Science, 300, 131-135.

[41]   Ryba, T., Hiratani, I., Lu, J.J., Itoh, M., Kulik, M., Zhang, J.F., Schulz, T.C., Robins, A.J., Dalton, S. and Gilbert, D.M. (2010) Evolutionarily Conserved Replication Timing Profiles Predict Long-Range Chromatin Interactions and Distinguish Closely Related Cell Types. Genome Research, 20, 761-770.

[42]   Agrelo, R., Souabni, A., Novatchkova, M., Haslinger, C., Leeb, M., Komnenovic, V., et al. (2009) SATB1 Defines the Developmental Context for Gene Silencing by Xist in Lymphoma and Embryonic Cells. Developmental Cell, 16, 507-516.

[43]   Panova, A.V., Nekrasov, E.D., Lagarkova, M.A., Kiselev, S.L. and Bogomazova, A.N. (2013) Late Replication of the Inactive X Chromosome Is Independent of the Compactness of Chromosome Territory in Human Pluripotent Stem Cells. Acta Naturae, 5, 54-61.

[44]   Nicodemi, M. and Prisco, A. (2007) Symmetry-Breaking Model for X-Chromosome Inactivation. Physical Review Letters, 98, 108104.

[45]   Mlynarczyk-Evans, S., Royce-Tolland, M., Alexander, M.K., Andersen, A.A., Kalantry, S., Gribnau, J. and Panning, B. (2006) X Chromosomes Alternate between Two States Prior to Random X-Inactivation. PLoS Biology, 4, e159.

[46]   Bacher, C.P., Guggiari, M., Brors, B., Augui, S., Clerc, P., Avner, P., Eils, R. and Heard, E. (2006) Transient Colocalization of X-Inactivation Centres Accompanies the Initiation of X Inactivation. Nature Cell Biology, 8, 293-299.

[47]   Augui, S., Filion, G.J., Huart, S., Nora, E., Guggiari, M., Maresca, M., Stewart, A.F. and Heard, E. (2007) Sensing X Chromosome Pairs before X Inactivation via a Novel X-Pairing Region of the Xic. Science, 318, 1632-1636.

[48]   Barakat, T.S., Jonkers, I., Monkhorst, K. and Gribnau, J. (2010) X-Changing Information on X Inactivation. Experimental Cell Research, 316, 679-687.

[49]   Masui, O., Bonnet, I., Le Baccon, P., Brito, I., Pollex, T., Murphy, N., Hupé, P., Barillot, E. and Belmont, A.S. (2011) Live-Cell Chromosome Dynamics and Outcome of X Chromosome Pairing Events during ES Cell Differentiation. Cell, 145, 447-458.

[50]   Scialdone, A. and Nicodemi, M. (2008) Mechanics and Dynamics of X-Chromosome Pairing at X Inactivation. PLoS Computational Biology, 4, e1000244.

[51]   Gartler, S.M. and Riggs, A.D. (1983) Mammalian X-Chromosome Inactivation. Annual Review of Genetics, 17, 155-190.

[52]   Engreitz, J.M., Pandya-Jones, A., McDonel, P., Shishkin, A., Sirokman, K., Surka, C., Kadri, S., Xing, J., Goren, A., Lander, E.S., Plath, K. and Guttman, M. (2013) The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread across the X Chromosome. Science, 341, 1237973.

[53]   Chan, K.M., Zhang, H., Malureanu, L., van Deursen, J. and Zhang, Z. (2011) Diverse Factors Are Involved in Maintaining X Chromosome Inactivation. Proceedings of the National Academy of Sciences of the United States of America, 108, 16699-16704.

[54]   Blewitt, M.E., Gendrel, A.V., Pang, Z., Sparrow, D.B., Whitelaw, N., Craig, J.M., Apedaile, A., Hilton, D.J., Dunwoodie, S.L., Brockdorff, N., Kay, G.F. and Whitelaw, E. (2008) SmcHD1, Containing a Structural-Maintenance-of-Chromosomes Hinge Domain, Has a Critical Role in X Inactivation. Nature Genetics, 40, 663-669.

[55]   Mould, A.W., Pang, Z., Pakusch, M., Tonks, I.D., Stark, M., Carrie, D., Mukhopadhyay, P., Seidel, A., Ellis, J.J., Deakin, J., Wakefield, M.J., Krause, L., Blewitt, M.E. and Kay, G.F. (2013) Smchd1 Regulates a Subset of Autosomal Genes Subject to Monoallelic Expression in Addition to Being Critical for X Inactivation. Epigenetics & Chromatin, 6, 19.

[56]   Gendrel, A.V., Apedaile, A., Coker, H., Termanis, A., Zvetkova, I., Godwin, J., et al. (2012) Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome. Developmental Cell, 23, 265-279.

[57]   Wong, C.C.Y., Caspi, A., Williams, B., Houts, R., Craig, I.W. and Mill, J. (2011) A Longitudinal Twin Study of Skewed X Chromosome-Inactivation. PLoS One, 6, e17873.

[58]   Christensen, K., Kristiansen, M., Hagen-Larsen, H., Skytthe, A., Bathum, L., Jeune, B., Andersen-Ranberg, K., Vaupel, J.W. and Orstavik, K.H. (2000) X-Linked Genetic Factors Regulate Hematopoietic Stem-Cell Kinetics in Females. Blood, 95, 2449-2451.

[59]   Sharp, A., Robinson, D. and Jacobs, P. (2000) Ageand Tissue-Specific Variation of X Chromosome Inactivation Ratios in Normal Women. Human Genetics, 107, 343-349.

[60]   Avner, P. and Heard, E. (2001) X-Chromosome Inactivation: Counting, Choice and Initiation. Nature Reviews Genetics, 2, 59-67.

[61]   Carrel, L. and Willard, H.F. (2005) X-Inactivation Profile Reveals Extensive Variability in X-Linked Gene Expression in Females. Nature, 434, 400-404.

[62]   Al Nadaf, S., Deakin, J.E., Gilbert, C., Robinson, T.J., Graves, J.A. and Waters, P.D. (2012) A Cross-Species Comparison of Escape from X Inactivation in Eutheria: Implications for Evolution of X Chromosome Inactivation. Chromosoma, 121, 71-78.

[63]   Grant, J., Mahadevaiah, S.K., Khil, P., Sangrithi, M.N., Royo, H., Duckworth, J., McCarrey, J.R., VandeBerg, J.L., Renfree, M.B., Taylor, W., Elgar, G., Camerini-Otero, R.D., Gilchrist, M.J. and Turner, J.M.A. (2012) Rsx Is a Metatherian RNA with Xist-Like Properties in X-Chromosome Inactivation. Nature, 487, 254-258.

[64]   Deakin, J.E., Chaumeil, J., Hore, T.A. and Marshall Graves, J.A. (2009) Unravelling the Evolutionary Origins of X Chromosome Inactivation in Mammals: Insights from Marsupials and Monotremes. Chromosome Research, 17, 671-685.

[65]   Braithwaite, R.W. and Lee, A.K. (1979) A Mammalian Example of Semelparity. American Naturalist, 113, 151-156.

[66]   Naylor, R., Richardson, S.J. and McAllan, B.M. (2008) Boom and Bust: A Review of the Physiology of the Marsupial Genus Antechinus. Journal of Comparative Physiology B, 178, 545-562.

[67]   Kraaijeveld, K., Kraaijeveld-Smit, F.J.L. and Adcock, G.J. (2003) Does Female Mortality Drive Male Semelparity in Dasyurid Marsupials? Proceedings of the Royal Society of London. Series B, 270, S251-S253.

[68]   Pan, Z. and Chang, C. (2012) Gender and the Regulation of Longevity: Implications for Autoimmunity. Autoimmunity Reviews, 11, A393-A403.

[69]   Barrett, E.L. and Richardson, D.S. (2011) Sex Differences in Telomeres and Lifespan. Aging Cell, 10, 913-921.

[70]   Gentilini, D., Mari, D., Castaldi, D., Remondini, D., Ogliari, G., Ostan, R., et al. (2013) Role of Epigenetics in Human Aging and Longevity: Genome-Wide DNA Methylation Profile in Centenarians and Centenarians’ Offspring. Age, 35, 1961-1973.

[71]   Gravina, S. and Vijg, J. (2010) Epigenetic Factors in Aging and Longevity. Pflügers Archiv, 459, 247-258.

[72]   West, J., Widschwendter, M. and Teschendorff, A.E. (2013) Distinctive Topology of Age-Associated Epigenetic Drift in the Human Interactome. Proceedings of the National Academy of Sciences of the United States of America, 110, 14138-14143.

[73]   Gentilini, D., Castaldi, D., Mari, D., Monti, D., Franceschi, C., Di Blasio, A.M. and Vitale, G. (2012) Age-Dependent Skewing of X Chromosome Inactivation Appears Delayed in Centenarians’ Offspring. Is There a Role for Allelic Imbalance in Healthy Aging and Longevity? Aging Cell, 11, 277-283.

[74]   Simmonds, M.J., Kavvoura, F.K., Brand, O.J., Newby, P.R., Jackson, L.E., Hargreaves, C.E., et al. (2014) Skewed X Chromosome Inactivation and Female Preponderance in Autoimmune Thyroid Disease: An Association Study and Meta-Analysis. Journal of Clinical Endocrinology & Metabolism, 99, E127-E131.

[75]   Uz, E., Loubiere, L.S., Gadi, V.K., Ozbalkan, Z., Stewart, J., Nelson, J.L. and Ozcelik, T. (2008) Skewed X-Chromosome Inactivation in Scleroderma. Clinical Reviews in Allergy & Immunology, 34, 352-355.

[76]   Cazzola, M., May, A., Bergamaschi, G., Cerani, P., Rosti, V. and Bishop, D.F. (2000) Familial-Skewed X-Chromosome Inactivation as a Predisposing Factor for Late-Onset X-Linked Sideroblastic Anemia in Carrier Females. Blood, 96, 4363-4365.

[77]   Chen, H.T., Wu, Y.C., Chen, S.T., Tsai, H.C. and Chien, Y.C. (2014) Androgen Receptor CAG Repeats, Non-Random X Chromosome Inactivation, and Loss of Heterozygosity at Xq25 in Relation to Breast Cancer Risk. BMC Cancer, 14, 144.

[78]   Franceschi, C., Motta, L., Valensin, S., Rapisarda, R., Franzone, A., Berardelli, M., et al. (2000) Do Men and Women Follow Different Trajectories to Reach Extreme Longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milano), 12, 77-84.

[79]   Hanna, J., Cheng, A.W., Saha, K., Kim, J., Lengner, C.J., Soldner, F., Cassady, J.P., Muffat, J., Carey, B.W. and Jaenisch, R. (2010) Human Embryonic Stem Cells with Biological and Epigenetic Characteristics Similar to Those of Mouse ESCs. Proceedings of the National Academy of Sciences of the United States of America, 107, 9222-9227.

[80]   Wang, W., Yang, J., Liu, H., Lu, D., Chen, X., Zenonos, Z., Campos, L.S., Rad, R., Guo, G., Zhang, S.J., Bradley, A. and Liu, P.T. (2011) Rapid and Efficient Reprogramming of Somatic Cells to Induced Pluripotent Stem Cells by Retinoic Acid Receptor Gamma and Liver Receptor Homolog 1. Proceedings of the National Academy of Sciences of the United States of America, 108, 18283-18288.

[81]   Tchieu, J., Kuoy, E., Chin, M.H., Trinh, H., Patterson, M., Sherman, S.P., et al. (2010) Female Human iPSCs Retain an Inactive X Chromosome. Cell Stem Cell, 7, 329-342.

[82]   Cheung, A.Y., Horvath, L.M., Carrel, L. and Ellis, J. (2012) X-Chromosome Inactivation in Rett Syndrome Human Induced Pluripotent Stem Cells. Frontiers in Psychiatry, 3, 24.