Project description:Mammals have evolved an XY sex chromosome system, resulting in dosage imbalance not only between sexes, but also between X-chromosome and autosome.
Project description:In mammals and several other taxa, the ability of males to cope with the limited synapsis of the X and Y chromosomes during prophase I of meiosis relies on the process of meiotic sex chromosome inactivation (MSCI). Components of the somatic DNA damage response machinery, including ATR, TOPBP1, MDC1 and BRCA1 play key roles in MSCI, although how they establish XY silencing remains incompletely understood. In particular, it remains unclear how DDR factors coordinate XY silencing with DNA repair, chromosome synapsis and the formation of the sex body, a distinct phase-separated sub-nuclear structure formed during prophase I to house the unsynapsed XY bivalent. Here we report a mutant mouse (Topbp1B5/B5), harboring mutations in the BRCT5 domain of Topbp1, that shows impaired XY silencing but grossly normal sex body formation. While Topbp1B5/B5 mice are viable, without detectable somatic defects, males are completely infertile. Distinct from mice lacking ATR or TOPBP1 specifically during meiosis, Topbp1B5/B5 males exhibit normal chromosome synapsis and canonical markers of DNA repair in early prophase I. ATR signaling is mostly intact in Topbp1B5/B5 spermatocytes, although specific ATR-dependent events are disrupted, including localization of the RNA:DNA helicase Senataxin to chromatin loops of the XY. Strikingly, while Topbp1B5/B5 spermatocytes are able to initiate MSCI the completion of gene silencing is defective, with a subset of X chromosome genes displaying distinct patterns of transcriptional deregulation. These findings suggest a non-canonical role for the ATR-TOPBP1 signaling axis in XY silencing dynamics at advanced stages in pachynema. This is the first DDR mutant that separates XY silencing from sex body formation, as well as TOPBP1’s role in spermatogenesis from its roles in organismal viability.
Project description:Abdominal aortic aneurysms (AAAs) are a prevalent and deadly human pathology with strong sexual dimorphism. Research demonstrates that sex hormones influence, but do not fully explain, male versus female AAA pathology. In addition to sex hormones, the X and Y sex chromosomes, and their unique complements of genes, may contribute to sexually dimorphic AAA pathology. Here, for the first time, we defined the effect of female (XX) versus male (XY) chromosome complement on AAA formation and rupture in phenotypically female mice using an established murine model. Abdominal aortas from female mice bearing the XY chromosome selectively expressed Y chromosome genes, while genes known to escape X-inactivation were higher in XX females. The majority of gene differences in XY females fell within inflammatory pathways. When XY females were infused with AngII, AAA incidences doubled and aneurysms ruptured. AAAs from XY females exhibited significant inflammation. Moreover, infusion of AngII to XY females augmented aortic activity of matrix metalloproteinases. Finally, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY compared to XX females. These results demonstrate that an XY sex chromosome complement profoundly influences aortic gene expression profiles and promotes AAA severity.
Project description:Objective-Aortic pathologies exhibit sexual dimorphism, with aneurysms in the ascending, thoracic and abdominal aorta (AAA) exhibiting higher prevalence in males. Despite lower incidence of aortic vascular disease in women, aneurysms progress rapidly. Mechanisms for these sex differences are unclear. We defined the role of sex chromosome complement and testosterone in regional development and progression of angiotensin II (AngII)-induced vascular pathologies. Approach and Results-We used transgenic male mice expressing Sry on an autosome to create low density lipoprotein receptor (Ldlr) deficient male mice with an XY or XX sex chromosome complement. Subjects were then sham operated or orcheictomized. Transcriptional profiling on abdominal aortas from XY or XX males demonstrated1746 genes influenced by sex chromosomes, sex hormones, or an interaction. A second cohort of animals was then infused with AngII for 28 days. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, while XX males developed discrete AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males, but not XX males exhibited adventitial thickening. We infused male XY and XX mice with saline or AngII and quantified mRNA abundance of key genes in thoracic versus abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in AAA aortic wall thickening in XY males with diffuse aortic pathology, while XX males had dilated focal AAAs. Conclusions-An XY sex chromosome complement mediates diffuse aortic pathology, while an XX sex chromosome complement contributes to discrete AngII-induced AAAs.
Project description:Mammals have evolved an XY sex chromosome system, resulting in dosage imbalance not only between sexes, but also between X-chromosome and autosome. mRNA profiles of 9 pairs of human endometrial carcinoma and adjacent tissues were generated by Illumina 100-nucleotide paired-end sequencing
Project description:We developed a cellular model to study sex differences in humans. Using somatic cells from a mosaic Kleinefelter patient, we generated isogenic human induced pluripotent stem cell lines with different sex chromosome complements – 47,XXY / 46,XX / 46,XY and 45,X0. 46, XX and 46, XY hiPSCs were differentiated to neural progenitor cells and compared.
Project description:Most autoimmune diseases have a higher incidence in women than men due to differences in sex hormones, sex chromosomes, or both. Female (XX) and male (XY) sex chromosome complements differ in parent-of-origin of the X chromosome, with females inheriting one each from the mother and father, while males inherit only one from the mother2. Here, we discovered that the paternal X (Xp) had higher DNA methylation than the maternal X (Xm) in autoantigen specific CD4+ T lymphocytes, potentially suppressing X gene expression in XX. Using the “Four Core Genotypes” model, the transcriptomes of autoantigen specific CD4+ T lymphocytes showed higher expression of many X genes in XY- than XX. Expression of toll-like receptor 7 (Tlr7) and forkhead box P3 (FoxP3), two X chromosome genes important in autoimmunity, was higher in XY- than XX, confirming genome wide methylation and transcription data. Thus, parent-of-origin differences in DNA methylation of X genes can lead to sexual dimorphisms in gene expression during autoimmunity.
Project description:We developed a cellular model to study sex differences in humans. Using somatic cells from a mosaic Kleinefelter patient, we generated isogenic human induced pluripotent stem cell lines with different sex chromosome complements – 47,XXY / 46,XX / 46,XY and 45,X0.