Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria

Biology of Sex Differences

Katherine Silkaitis¹  Bernardo Lemos¹ 

[1] Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115-6021, USA

关键词: Sex difference;    X chromosome;    Y chromosome;    Heterochromatin;    Sex chromosomes;    Sexual dimorphisms;    Drosophila;    Gene expression regulation;   

Others  :  792907
DOI  :  10.1186/2042-6410-5-2

 received in 2013-11-04, accepted in 2013-12-29,  发布年份 2014

【 摘 要 】

Several autoimmune and neurological diseases exhibit a sex bias, but discerning the causes and mechanisms of these biases has been challenging. Sex differences begin to manifest themselves in early embryonic development, and gonadal differentiation further bifurcates the male and female phenotypes. Even at this early stage, however, there is evidence that males and females respond to environmental stimuli differently, and the divergent phenotypic responses may have consequences later in life. The effect of prenatal nutrient restriction illustrates this point, as adult women exposed to prenatal restrictions exhibited increased risk factors of cardiovascular disease, while men exposed to the same condition did not. Recent research has examined the roles of sex-specific genes, hormones, chromosomes, and the interactions among them in mediating sex-biased phenotypes. Such research has identified testosterone, for example, as a possible protective agent against autoimmune disorders and an XX chromosome complement as a susceptibility factor in murine models of lupus and multiple sclerosis. Sex-biased chromatin is an additional and likely important component. Research suggesting a role for X and Y chromosome heterochromatin in regulating epigenetic states of autosomes has highlighted unorthodox mechanisms of gene regulation. The crosstalk between the Y chromosomes and autosomes may be further mediated by the mitochondria. The organelles have solely maternal transmission and exert differential effects on males and females. Altogether, research supports the notion that the interaction between sex-biased elements might exert novel regulatory functions in the genome and contribute to sex-specific susceptibilities to autoimmune and neurological diseases.

【 授权许可】

   
2014 Silkaitis and Lemos; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Washburn TC, Medearis DN, Childs B: Sex differences in susceptibility to infections. Pediatrics 1965, 35:57-64.
• [2]Beeson PB: Age and sex associations of 40 autoimmune diseases. Am J Med 1994, 96:457-462.
• [3]Voskuhl R: Sex differences in autoimmune disease. Biol Sex Differ 2011, 2:1. BioMed Central Full Text
• [4]Arnold AP, Chen X, Itoh Y: What a difference an X or Y makes: sex chromosomes, gene dose, and epigenetics in sexual differentiation. Handb Exp Pharmacol 2012, 214:67-88.
• [5]Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M: Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007, 317:121-124.
• [6]Madan V, Lear JT, Szeimies R-M: Non-melanoma skin cancer. Lancet 2010, 375:673-685.
• [7]Turtzo L, McCullough L: Sex-specific responses to stroke. Future Neurol 2010, 5:47-59.
• [8]Ranz JM, Castillo-Davis C, Meiklejohn CD, Hartl DL: Sex-dependent gene expression and evolution of the Drosophila transcriptome. Science 2003, 300(5626):1742-1745.
• [9]Parsch J, Ellegren H: The evolutionary causes and consequences of sex-biased gene expression. Nat Rev Genet 2013, 14:83-87.
• [10]Rand DM, Clark AG, Kann LM: Sexually antagonistic cytonuclear fitness interactions in Drosophila melanogaster. Genetics 2001, 159:173-187.
• [11]Innocenti P, Morrow EH, Dowling DK: Experimental evidence supports a sex-specific selective sieve in mitochondrial genome evolution. Science 2011, 332:845-848.
• [12]Gemmell NJ, Metcalf VJ, Allendorf FW: Mother's curse: the effect of mtDNA on individual fitness and population viability. Trends Ecol Evol 2004, 19:238-244.
• [13]Rice W: Sex chromosomes and the evolution of sexual dimorphism. Evolution (N Y) 1984, 38:735-742.
• [14]Fish EN: The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 2008, 8:737-744.
• [15]Soldin OP, Mattison DR: Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2009, 48:143-157.
• [16]Houtchens MK: Pregnancy and multiple sclerosis. Semin Neurol 2007, 27:434-441.
• [17]Chen X, McClusky R, Chen J, Beaven SW, Tontonoz P, Arnold AP, Reue K: The number of X chromosomes causes sex differences in adiposity in mice. PLoS Genet 2012, 8:e1002709.
• [18]Chen X, McClusky R, Itoh Y, Reue K, Arnold AP: X and Y chromosome complement influence adiposity and metabolism in mice. Endocrinology 2013, 154:1092-1104.
• [19]Invernizzi P, Miozzo M, Selmi C, Persani L, Battezzati PM, Zuin M, Lucchi S, Meroni PL, Marasini B, Zeni S, Watnik M, Grati FR, Simoni G, Gershwin ME, Podda M: X chromosome monosomy: a common mechanism for autoimmune diseases. J Immunol 2005, 175:575-578.
• [20]Sasidhar MV, Itoh N, Gold SM, Lawson GW, Voskuhl RR: The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY. Ann Rheum Dis 2012, 71:1418-1422.
• [21]Charchar FJ, Bloomer LDS, Barnes TA, Cowley MJ, Nelson CP, Wang Y, Denniff M, Debiec R, Christofidou P, Nankervis S, Dominiczak AF, Bani-Mustafa A, Balmforth AJ, Hall AS, Erdmann J, Cambien F, Deloukas P, Hengstenberg C, Packard C, Schunkert H, Ouwehand WH, Ford I, Goodall AH, Jobling MA, Samani NJ, Tomaszewski M: Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet 2012, 379:915-922.
• [22]Selmi C: The X in sex: how autoimmune diseases revolve around sex chromosomes. Best Pract Res Clin Rheumatol 2008, 22:913-922.
• [23]Sawalha AH, Harley JB, Scofield RH: Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. J Autoimmun 2009, 33:31-34.
• [24]Sun S, Horino S, Itoh-Nakadai A, Kawabe T, Asao A, Takahashi T, So T, Funayama R, Kondo M, Saitsu H, Matsumoto N, Nakayama K, Ishii N: Y chromosome-linked B and NK cell deficiency in mice. J Immunol 2013, 190:6209-6220.
• [25]Goris A, Liston A: The immunogenetic architecture of autoimmune disease. Cold Spring Harb Perspect Biol 2012, 4:1-14.
• [26]Arnold AP: The end of gonad-centric sex determination in mammals. Trends Genet 2011, 28:55-61.
• [27]Goodfellow P, Lovell-Badge R: SRY and sex determination in mammals. Annu Rev Genet 1993, 27:71-91.
• [28]Sekido R, Lovell-Badge R: Sex determination and SRY: down to a wink and a nudge? Trends Genet 2009, 25:19-29.
• [29]Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P: Primordial germ cells and sex determination in mammals. In Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. [http://www.ncbi.nlm.nih.gov/books/NBK26940 webcite]
• [30]Koopman P: The delicate balance between male and female sex determining pathways: potential for disruption of early steps in sexual development. Int J Androl 2010, 33:252-258.
• [31]Lahr G, Maxson SC, Mayer A, Just W, Pilgrim C, Reisert I: Transcription of the Y chromosomal gene, Sry, in adult mouse brain. Brain Res Mol Brain Res 1995, 33:179-182.
• [32]Clepet C, Schater AJ, Sinclair AH, Palmer MS, Lovell-Badge R, Goodfellow PN: The human SRY transcript. Hum Mol Genet 1993, 2:2007-2012.
• [33]Dewing P, Chiang CWK, Sinchak K, Sim H, Fernagut P-O, Kelly S, Chesselet M-F, Micevych PE, Albrecht KH, Harley VR, Vilain E: Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol 2006, 16:415-420.
• [34]Wu J, Chen K, Li Y, Lau Y, Shih J: Regulation of monoamine oxidase A by the SRY gene on the Y chromosome. FASEB J 2009, 23:4029-4038.
• [35]Czech DP, Lee J, Sim H, Parish CL, Vilain E, Harley VR: The human testis-determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism. J Neurochem 2012, 122:260-271.
• [36]Kalantry S: Recent advances in X-chromosome inactivation. J Cell Physiol 2011, 226:1714-1718.
• [37]Payer B, Lee JT: X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet 2008, 42:733-772.
• [38]Lucchesi JC, Kelly WG, Panning B: Chromatin remodeling in dosage compensation. Annu Rev Genet 2005, 39:615-651.
• [39]Disteche CM: Dosage compensation of the sex chromosomes. Annu Rev Genet 2012, 46:537-560.
• [40]Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E: Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 2004, 303:644-649.
• [41]Wutz A: Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet 2011, 12:542-553.
• [42]Carrel L, Willard HF: X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005, 434:400-404.
• [43]Yang F, Babak T, Shendure J, Disteche CM: Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res 2010, 20(5):614-622.
• [44]Hewagama A, Gorelik G, Patel D, Liyanarachchi P, McCune WJ, Somers E, Gonzalez-Rivera T, Strickland F, Richardson B: Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun 2013, 41:60-71.
• [45]Lleo A, Oertelt-Prigione S, Bianchi I, Caliari L, Finelli P, Miozzo M, Lazzari R, Floreani A, Donato F, Colombo M, Gershwin ME, Podda M, Invernizzi P: Y chromosome loss in male patients with primary biliary cirrhosis. J Autoimmun 2013, 41:87-91.
• [46]Thornhill AR, Burgoyne PS: A paternally imprinted X chromosome retards the development of the early mouse embryo. Development 1993, 118:171-174.
• [47]Davies W, Isles A, Smith R, Karunadasa D, Burrmann D, Humby T, Ojarikre O, Biggin C, Skuse D, Burgoyne P, Wilkinson L: Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nat Genet 2005, 37:625-629.
• [48]Fearon E, Winkelstein J, Civin C, Pardoll DM, Vogelstein B: Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. N Engl J Med 1987, 316:427-431.
• [49]Wengler G, Gorlin J, Williamson J, Rosen F, Bing D: Nonrandom inactivation of the X chromosome in early lineage hematopoietic cells in carriers of Wiskott-Aldrich syndrome. Blood 1995, 85:2471-2477.
• [50]Ozbalkan Z, Bagişlar S, Kiraz S, Akyerli CB, Ozer HTE, Yavuz S, Birlik AM, Calgüneri M, Ozçelik T: Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum 2005, 52:1564-1570.
• [51]Buller R, Sood A, Lallas T, Buekers T, Skilling J: Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. J Natl Cancer Inst 1999, 91:1508-1509.
• [52]Kristiansen M, Langerød A, Knudsen GP, Weber BL, Børresen-Dale AL, Orstavik KH: High frequency of skewed X inactivation in young breast cancer patients. J Med Genet 2002, 39:30-33.
• [53]Straub T, Becker PB: Transcription modulation chromosome-wide: universal features and principles of dosage compensation in worms and flies. Curr Opin Genet Dev 2011, 21:147-153.
• [54]Smith-Bouvier DL, Divekar AA, Sasidhar MV, Du S, Tiwari-Woodruff SK, King JK, Arnold AP, Singh RR, Voskuhl RR: A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 2008, 205:1099-1108.
• [55]Persani L, Bonomi M, Lleo A, Pasini S, Civardi F, Bianchi I, Campi I, Finelli P, Miozzo M, Castronovo C, Sirchia S, Gershwin ME, Invernizzi P: Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis. J Autoimmun 2012, 38:J193-J196.
• [56]Zvetkova I, Apedaile A, Ramsahoye B, Mermoud JE, Crompton LA, John R, Feil R, Brockdorff N: Global hypomethylation of the genome in XX embryonic stem cells. Nat Genet 2005, 37:1274-1279.
• [57]Durcova-Hills G, Hajkova P, Sullivan S, Barton S, Surani MA, McLaren A: Influence of sex chromosome constitution on the genomic imprinting of germ cells. Proc Natl Acad Sci USA 2006, 103:11184-11188.
• [58]Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N, Abe K, Ogura A, Wilhelm D, Koopman P, Nozaki M, Kanai Y, Shinkai Y, Tachibana M: Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 2013, 341:1106-1109.
• [59]Muller H: Types of visible variations induced by X-rays in Drosophila. J Genet 1930, 22:299-334.
• [60]Wijchers PJ, Yandim C, Panousopoulou E, Ahmad M, Harker N, Saveliev A, Burgoyne PS, Festenstein R: Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well. Dev Cell 2010, 19:477-484.
• [61]Mittwoch U: Blastocysts prepare for the race to be male. Hum Reprod 1993, 8:1550-1555.
• [62]Gutiérrez-Adán A, Perez-Crespo M, Fernandez-Gonzalez R, Ramirez MA, Moreira P, Pintado B, Lonergan P, Rizos D: Developmental consequences of sexual dimorphism during pre-implantation embryonic development. Reprod Domest Anim 2006, 41(Suppl 2):54-62.
• [63]Bermejo-Alvarez P, Rizos D, Lonergan P, Gutierrez-Adan A: Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes. Reproduction 2011, 141:801-808.
• [64]Dewing P, Shi T, Horvath S, Vilain E: Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Mol Brain Res 2003, 118:82-90.
• [65]Gilbert SF: Chromosomal sex determination in Drosophila. In Developmental Biology. 6th edition. Edited by Gilbert SF. Sunderland: Sinauer Associates; 2000. [http://www.ncbi.nlm.nih.gov/books/NBK10025 webcite]
• [66]Prahlad V, Pilgrim D, Goodwin EB: Roles for mating and environment in C. elegans sex determination. Science 2003, 302:1046-1049.
• [67]Gilbert SF: Chromosomal sex determination in mammals. In Developmental Biology. 6th edition. Edited by Gilbert SF. Sunderland: Sinauer; 2000. [http://www.ncbi.nlm.nih.gov/books/NBK9967 webcite]
• [68]Gravholt CH, Stochholm K: The epidemiology of Turner syndrome. Int Congr Ser 2006, 1298:139-145.
• [69]Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A: Clinical review: Klinefelter syndrome—a clinical update. J Clin Endocrinol Metab 2013, 98:20-30.
• [70]Bardsley MZ, Kowal K, Levy C, Gosek A, Ayari N, Tartaglia N, Lahlou N, Winder B, Grimes S, Ross JL: 47, XYY syndrome: clinical phenotype and timing of ascertainment. J Pediatr 2013, 163:1085-1094.
• [71]Morris JK, Alberman E, Scott C, Jacobs P: Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet 2008, 16:163-170.
• [72]Lucchesi J, Rawls J, Maroni G: Gene dosage compensation in metafemales (3X; 2A) of Drosophila. Nature 1974, 248:564-567.
• [73]Neeley JC: Some environmental influences on metafemale viability in Drosophila melanogaster. J Hered 1971, 62:334-338.
• [74]Birchler J, Hiebert J, Krietzman M: Gene expression in adult metafemales of Drosophila melanogaster. Genetics 1989, 122:869-879.
• [75]Frost J: The occurrence of partially fertile triploid metafemales in Drosophila melanogaster. Proc Natl Acad Sci USA 1960, 46:47-51.
• [76]Lovell-Badge R, Robertson E: XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy. Development 1990, 109:635-646.
• [77]Wijchers PJ, Festenstein RJ: Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends Genet 2011, 27:132-140.
• [78]Penaloza C, Estevez B, Orlanski S, Sikorska M, Walker R, Smith C, Smith B, Lockshin RA, Zakeri Z: Sex of the cell dictates its response: differential gene expression and sensitivity to cell death inducing stress in male and female cells. FASEB J 2009, 23:1869-1879.
• [79]Case L, Wall E, Dragon J, Saligrama N, Krementsov DN, Moussawi M, Zachary J, Huber S, Blanekenhorn E, Teuscher C: The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. Genome Res 2013, 23(9):1-12.
• [80]Hewagama A, Richardson B: The genetics and epigenetics of autoimmune diseases. J Autoimmun 2009, 33:3-11.
• [81]Lekpa FK, Ndongo S, Tiendrebeogo J, Ndao AC, Daher A, Pouye A, Ka MM, Diop TM: Rheumatoid arthritis in Senegal: a comparison between patients coming from rural and urban areas, in an urban tertiary health care center in Senegal. Clin Rheumatol 2012, 31:1617-1620.
• [82]Xu K, Peng H, Zhou M, Wang W, Li R, Zhu K-K, Zhang M, Wen P-F, Pan H-F, Ye D-Q: Association study of TRAF1/C5 polymorphism (rs10818488) with susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Gene 2013, 517:46-54.
• [83]Nakada K, Sato A, Yoshida K, Morita T, Tanaka H, Inoue S-I, Yonekawa H, Hayashi J-I: Mitochondria-related male infertility. Proc Natl Acad Sci USA 2006, 103:15148-15153.
• [84]Camus MF, Clancy DJ, Dowling DK: Mitochondria, maternal inheritance, and male aging. Curr Biol 2012, 22:1717-1721.
• [85]Rand DM, Haney RA, Fry AJ: Cytonuclear coevolution: the genomics of cooperation. Trends Ecol Evol 2004, 19:645-653.
• [86]Zeyl C, Andreson B, Weninck E: Nuclear-mitochondrial epistasis for fitness in Saccharomyces cerevisiae. Evolution 2005, 59:910-914.
• [87]Kenyon L, Moraes CT: Expanding the functional human mitochondrial DNA database by the establishment of primate xenomitochondrial cybrids. Proc Natl Acad Sci 1997, 94(17):9131-9135.
• [88]Stouffs K, Lissens W, Tournaye H, Haentjens P: What about gr/gr deletions and male infertility? Systematic review and meta-analysis. Hum Reprod Update 2011, 17:197-209.
• [89]Hoskins R, Smith CD, Carlson JW, Carvalho AB, Halpern A, Kaminker JS, Kennedy C, Mungall CJ, Sullivan BA, Sutton GG, Yasuhara JC, Wakimoto BT, Myers EW, Celniker SE, Rubin GM, Karpen GH: Heterochromatic sequences in a Drosophila whole-genome shotgun assembly. Genome Biol 2002, 3:RESEARCH0085.
• [90]Koerich LB, Wang X, Clark AG, Carvalho AB: Low conservation of gene content in the Drosophila Y chromosome. Nature 2008, 456:949-951.
• [91]Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S, Fitzgerald S, Gil L, García-Girón C, Gordon L, Hourlier T, Hunt S, Juettemann T, Kähäri AK, Keenan S, Komorowska M, Kulesha E, Longden I, Maurel T, McLaren WM, Muffato M, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, et al.: Ensembl 2013. Nucleic Acids Res 2013, 41(Database issue):D48-D55.
• [92]Rohmer C, David JR, Moreteau B, Joly D: Heat induced male sterility in Drosophila melanogaster: adaptive genetic variations among geographic. J Exp Biol 2004, 207(Pt 16):2735-2743.
• [93]David JR, Araripe LO, Chakir M, Legout H, Lemos B, Pétavy G, Rohmer C, Joly D, Moreteau B: Male sterility at extreme temperatures: a significant but neglected phenomenon for understanding Drosophila climatic adaptations. J Evol Biol 2005, 18:838-846.
• [94]Lemos B, Araripe LO, Hartl DL: Polymorphic Y chromosomes harbor cryptic variation with manifold functional consequences. Science 2008, 319:91-93.
• [95]Chippindale AK, Rice WR: Y chromosome polymorphism is a strong determinant of male fitness in Drosophila melanogaster. Proc Natl Acad Sci USA 2001, 98:5677-5682.
• [96]Pertile M, Graham A: Rapid evolution of mouse Y centromere repeat DNA belies recent sequence stability. Genome Res 2009, 19:2202-2213.
• [97]Dimitri P, Pisano C: Position effect variegation in Drosophila melanogaster: relationship between suppression effect and the amount of Y chromosome. Genetics 1989, 122:793-800.
• [98]Lemos B, Branco AT, Hartl DL: Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict. Proc Natl Acad Sci USA 2010, 107:15826-15831.
• [99]Paredes S, Branco AT, Hartl DL, Maggert KA, Lemos B: Ribosomal DNA deletions modulate genome-wide gene expression: “rDNA–sensitive” genes and natural variation. PLoS Genet 2011, 7:10.
• [100]Francisco F, Lemos B: How do Y-chromosomes modulate genome-wide epigenetic states: genome folding, chromatin sinks, and gene expression. J Genomics 2014. in press
• [101]Branco AT, Hartl DL, Lemos B: Chromatin-associated proteins HP1 and Mod(mdg4) modify Y-linked regulatory variation in the Drosophila testis. Genetics 2013, 194(3):609-618.
• [102]Taddei A, Hediger F, Neumann FR, Gasser SM: The function of nuclear architecture: a genetic approach. Annu Rev Genet 2004, 38:305-345.
• [103]Ye Q, Worman HJ: Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1. J Biol Chem 1996, 271:14653-14656.
• [104]Liu L-P, Ni J-Q, Shi Y-D, Oakeley EJ, Sun F-L: Sex-specific role of Drosophila melanogaster HP1 in regulating chromatin structure and gene transcription. Nat Genet 2005, 37:1361-1366.
• [105]Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH: Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 2008, 105:17046-17049.
• [106]Lumey LH, Stein AD, Kahn HS, Romijn JA: Lipid profiles in middle-aged men and women after famine exposure during gestation: the Dutch Hunger Winter Families Study. Am J Clin Nutr 2009, 89:1737-1743.
• [107]Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD, Slagboom PE, Heijmans BT: DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009, 18:4046-4053.
• [108]Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, Thurston A, Huntley JF, Rees WD, Maloney CA, Lea RG, Craigon J, McEvoy TG, Young LE: DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 2007, 104:19351-19356.
• [109]Mueller BR, Bale TL: Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 2008, 28:9055-9065.
• [110]Lillycrop KA, Phillips ES, Torrens C, Hanson MA, Jackson AA, Burdge GC: Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr 2008, 100:278-282.
• [111]Jiang P-P, Hartl DL, Lemos B: Y not a dead end: epistatic interactions between Y-linked regulatory polymorphisms and genetic background affect global gene expression in Drosophila melanogaster. Genetics 2010, 186:109-118.
• [112]Case LK, Toussaint L, Moussawi M, Roberts B, Saligrama N, Brossay L, Huber SA, Teuscher C: Chromosome Y regulates survival following murine coxsackievirus B3 infection. G3 (Bethesda) 2012, 2:115-121.
• [113]Orton S-M, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, Ebers GC: Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006, 5:932-936.
• [114]Boström I, Stawiarz L, Landtblom A-M: Age-specific sex ratio of multiple sclerosis in the National Swedish MS Register (SMSreg). Mult Scler 2013, 19(1):46-52.
• [115]Harbo HF, Gold R, Tintoré M: Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord 2013, 6:237-248.
• [116]Bebo B Jr, Zelinka-Vincent E, Adamus G, Amundson D, Vandenbark A, Offner H: Gonadal hormones influence the immune response to PLP 139–151 and the clinical course of relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 1998, 84:122-130.
• [117]Foster SC, Daniels C, Bourdette DN, Bebo BF: Dysregulation of the hypothalamic–pituitary–gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neuroimmunol 2003, 140:78-87.
• [118]Palaszynski K, Loo K, Ashouri J, Liu H, Voskuhl RR: Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neuroimmunol 2004, 146:144-152.
• [119]Kantarci O, Goris A, Hebrink D, Heggarty S, Cunningham S, Alloza I, Atkinson E, de Andrade M, McMurray C, Graham C, Hawkins S, Billiau A, Dubois B, Weinshenker B, Vandenbroeck K: IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis. Genes Immun 2005, 6:153-161.
• [120]Camiña-Tato M, Morcillo-Suare C, Bustamante M, Ortega I, Navarro A, Muntasell A, Lopez-Botet M, Sanchez A, Carmona P, Julia E, Tortola M, Audi L, Oksenberg J, Martin R, Montalban X, Comabella M: Gender-associated differences of perforin polymorphisms in the susceptibility to multiple sclerosis. J Immunol 2010, 185:5392-5404.
• [121]Spach KM, Blake M, Bunn JY, McElvany B, Noubade R, Blankenhorn EP, Teuscher C: Cutting edge: the Y chromosome controls the age-dependent experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice. J Immunol 2009, 182:1789-1793.
• [122]Praktiknjo SD, Llamas B, Scott-Boyer M-P, Picard S, Robert F, Langlais D, Haibe-Kains B, Faubert D, Silversides DW, Deschepper CF: Novel effects of chromosome Y on cardiac regulation, chromatin remodeling, and neonatal programming in male mice. Endocrinology 2013, 154:4746-4756.
• [123]Llamas B, Verdugo RA, Churchill GA, Deschepper CF: Chromosome Y variants from different inbred mouse strains are linked to differences in the morphologic and molecular responses of cardiac cells to postpubertal testosterone. BMC Genomics 2009, 10:150. BioMed Central Full Text
• [124]Frey N, Olson EN: Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 2003, 65:45-79.