Castration Model Illuminates Sex Differences in Healthy Aging: Insights from Metabolome and Transcriptome Analyses
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252625 | GEO | 2025/10/01
REPOSITORIES: GEO
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Project description:The goal of our study was to evaluate at the systems-level, the effect of sex hormones on thymic epithelial cells (TECs). To this end, we sequenced the transcriptome of cortical and medullary TECs (cTECs and mTECs) from three groups of 6 month-old mice: males, females and males castrated at four weeks of age. In parallel, we analyzed variations in the size of TEC subsets in those three groups between 1 and 12 months of age. We report that sex hormones have pervasive effects on the transcriptome of TECs: the number of differentially expressed genes was 1,440 in cTECs and 1,783 in mTECs. Sexual dimorphism was particularly conspicuous in cTECs. Male cTECs displayed low proliferation rates that correlated with low expression of Foxn1 and its main targets. Furthermore, male cTECs expressed relatively low levels of genes instrumental in thymocyte expansion (e.g., Dll4) and positive selection (Psmb11 and Ctsl). Nevertheless, cTECs were more abundant in males than females. Accumulation of cTECs in males correlated with differential expression of genes regulating cell survival and cell differentiation. Unexpectedly, we observed that female and male sex hormones repressed promiscuous gene expression in mTECs. Since sex hormones did not affect the expression of Aire per se, they must impinge on the activity of unidentified regulator(s) of promiscuous gene expression in mTECs. The sexual dimorphism of TECs highlighted here may be mechanistically linked to the well-recognized sex differences in susceptibility to infections and autoimmune diseases.
2015-11-26 | GSE66873 | GEO
Project description:Multiple sclerosis (MS) is a T-cell mediated autoimmune disease that has a sexually dimorphic pattern in disease susceptibility. Consistent with many autoimmune diseases, females are more susceptible than males to MS. Sexual dimorphisms may be due to differences in sex hormones, sex chromosome genes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape the dosage compensation mechanism of X inactivation and have higher expression in females (XX) compared to males (XY). According to the high throughput analysis, the top sexually dimorphic gene with higher expression in CD4+ T cells from females (vs. males) and from XX mice (vs. XY) was Kdm6a, a histone demethylase and transcription factor on the X chromosome. Deletion of Kdm6a specifically in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, this demonstrates that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.
2019-10-18 | GSE121703 | GEO
Project description:Multiple sclerosis (MS) is a T-cell mediated autoimmune disease that has a sexually dimorphic pattern in disease susceptibility. Consistent with many autoimmune diseases, females are more susceptible than males to MS. Sexual dimorphisms may be due to differences in sex hormones, sex chromosome genes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape the dosage compensation mechanism of X inactivation and have higher expression in females (XX) compared to males (XY). According to the high throughput analysis, the top sexually dimorphic gene with higher expression in CD4+ T cells from females (vs. males) and from XX mice (vs. XY) was Kdm6a, a histone demethylase and transcription factor on the X chromosome. Deletion of Kdm6a specifically in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, this demonstrates that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.
2019-10-18 | GSE128615 | GEO
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.
2018-07-22 | GSE102143 | GEO
Project description:sex-specific role of p38-MAPK in EAE is regulated by estrogen receptor alpha; Biological sex is a critical factor in regulating immune function. A striking example of this is the higher prevalence of autoimmune diseases such as multiple sclerosis (MS) and lupus in females compared to males. While many studies have implicated the role of sex hormones such as estrogens and androgens in these sex differences, surprisingly little is known about other molecular pathways that underlie sex differences or interact with sex hormones. We have previously shown that conditional ablation of p38α MAP kinase signaling in myeloid cells (p38αCKO) was protective in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), in female but not male mice. This sex difference was dependent on the presence of sex hormones, leading us to hypothesize that the pathogenic function of p38α in EAE depends on estrogen signaling via one of the two nuclear estrogen receptors, encoded by Esr1 and Esr2. To test this hypothesis, we performed experiments with p38αCKO macrophages, which demonstrated that the effects of estradiol and p38α were independent of one another in vitro. Since many sex hormone effects are lost in vitro, we generated p38αCKO mice lacking either Esr1 or Esr2, and evaluated their EAE susceptibility in vivo. Myeloid-specific deletion of Esr1 abrogated protection in p38αCKO females, although global deletion of Esr1 and Esr2 did not. Moreover, global or myeloid-specific disruption of Esr1 unexpectedly promoted protection from EAE in p38αCKO males. Mechanistically, Esr1 deletion resulted in partial reprogramming of p38α-dependent transcriptional modules in male macrophages, in particular those regulated by TGFβ, BRD4, and SMARCA4. These results demonstrate that estrogen signaling in myeloid cells plays an important sex-specific role in programming their dependence on specific intracellular signaling pathways in the context of autoimmune disease pathogenesis, suggesting potential avenues for sex-specific therapeutics or combinatorial approaches for the treatment of such diseases.
2020-03-05 | GSE146370 | GEO
Project description:Multiple sclerosis (MS) exhibits a sex difference in susceptibility with females affected more frequently than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosomes, some X chromosome genes escape X-inactivation and have higher expression in females (XX) compared to males (XY). The Genotype Tissue Expression Project (GTEx) has found that 37% of all genes exhibit sex biased expression which is tissue-specific and cell-specific, but the etiology and ramifications of this sex difference remain unknown. Kdm6a is an X chromosome gene that escapes X-inactivation and encodes for a histone demethylase which can modulate autosomal gene expression. Given the important role of microglia in neurodegenerative diseases, we created a tissue-specific and cell-specific conditional knock out (cKO) of Kdm6a in microglia and induced experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model for MS. Deletion of Kdm6a in microglia ameliorated EAE. Gene expression analysis of spinal cord microglia during EAE in the Kdm6a cKO revealed downregulation of degeneration associated microglial markers and upregulation of resting microglial markers compared to EAE in wild type. Genome wide transcriptome analyses demonstrated reversal of the EAE associated transcriptome in microglia in Kdm6a cKO mice, instead aligning with that of the transcriptome of microglia in healthy mice. Finally, there was a sex difference in the effect of selective deletion of Kdm6a in microglia whereby EAE was abrogated in females more significantly than in males. Together, this demonstrates that the X-escapee Kdm6a is disease promoting in microglia of females with neurodegenerative disease.
2025-10-15 | GSE246008 | GEO
Project description:Multiple sclerosis (MS) exhibits a sex difference in susceptibility with females affected more frequently than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosomes, some X chromosome genes escape X-inactivation and have higher expression in females (XX) compared to males (XY). The Genotype Tissue Expression Project (GTEx) has found that 37% of all genes exhibit sex biased expression which is tissue-specific and cell-specific, but the etiology and ramifications of this sex difference remain unknown. Kdm6a is an X chromosome gene that escapes X-inactivation and encodes for a histone demethylase which can modulate autosomal gene expression. Given the important role of microglia in neurodegenerative diseases, we created a tissue-specific and cell-specific conditional knock out (cKO) of Kdm6a in microglia and induced experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model for MS. Deletion of Kdm6a in microglia ameliorated EAE. Gene expression analysis of spinal cord microglia during EAE in the Kdm6a cKO revealed downregulation of degeneration associated microglial markers and upregulation of resting microglial markers compared to EAE in wild type. Genome wide transcriptome analyses demonstrated reversal of the EAE associated transcriptome in microglia in Kdm6a cKO mice, instead aligning with that of the transcriptome of microglia in healthy mice. Finally, there was a sex difference in the effect of selective deletion of Kdm6a in microglia whereby EAE was abrogated in females more significantly than in males. Together, this demonstrates that the X-escapee Kdm6a is disease promoting in microglia of females with neurodegenerative disease.
2025-10-15 | GSE221400 | GEO
Project description:Multiple sclerosis (MS) exhibits a sex difference in susceptibility with females affected more frequently than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosomes, some X chromosome genes escape X-inactivation and have higher expression in females (XX) compared to males (XY). The Genotype Tissue Expression Project (GTEx) has found that 37% of all genes exhibit sex biased expression which is tissue-specific and cell-specific, but the etiology and ramifications of this sex difference remain unknown. Kdm6a is an X chromosome gene that escapes X-inactivation and encodes for a histone demethylase which can modulate autosomal gene expression. Given the important role of microglia in neurodegenerative diseases, we created a tissue-specific and cell-specific conditional knock out (cKO) of Kdm6a in microglia and induced experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model for MS. Deletion of Kdm6a in microglia ameliorated EAE. Gene expression analysis of spinal cord microglia during EAE in the Kdm6a cKO revealed downregulation of degeneration associated microglial markers and upregulation of resting microglial markers compared to EAE in wild type. Genome wide transcriptome analyses demonstrated reversal of the EAE associated transcriptome in microglia in Kdm6a cKO mice, instead aligning with that of the transcriptome of microglia in healthy mice. Finally, there was a sex difference in the effect of selective deletion of Kdm6a in microglia whereby EAE was abrogated in females more significantly than in males. Together, this demonstrates that the X-escapee Kdm6a is disease promoting in microglia of females with neurodegenerative disease.
2025-10-15 | GSE220566 | GEO
Project description:Multiple sclerosis (MS) exhibits a sex difference in susceptibility with females affected more frequently than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosomes, some X chromosome genes escape X-inactivation and have higher expression in females (XX) compared to males (XY). The Genotype Tissue Expression Project (GTEx) has found that 37% of all genes exhibit sex biased expression which is tissue-specific and cell-specific, but the etiology and ramifications of this sex difference remain unknown. Kdm6a is an X chromosome gene that escapes X-inactivation and encodes for a histone demethylase which can modulate autosomal gene expression. Given the important role of microglia in neurodegenerative diseases, we created a tissue-specific and cell-specific conditional knock out (cKO) of Kdm6a in microglia and induced experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model for MS. Deletion of Kdm6a in microglia ameliorated EAE. Gene expression analysis of spinal cord microglia during EAE in the Kdm6a cKO revealed downregulation of degeneration associated microglial markers and upregulation of resting microglial markers compared to EAE in wild type. Genome wide transcriptome analyses demonstrated reversal of the EAE associated transcriptome in microglia in Kdm6a cKO mice, instead aligning with that of the transcriptome of microglia in healthy mice. Finally, there was a sex difference in the effect of selective deletion of Kdm6a in microglia whereby EAE was abrogated in females more significantly than in males. Together, this demonstrates that the X-escapee Kdm6a is disease promoting in microglia of females with neurodegenerative disease.
2025-10-15 | GSE261726 | GEO
Project description:Differences in adipose tissue deposition and properties between pig male sex categories, i.e., entire male, immunocastrated and surgically castrated pigs are relatively well characterized, whereas the underlying genetic mechanisms are still not fully understood. To gain the knowledge about the genetic regulation of the differences in adipose tissue deposition, RNA-sequencing approach was used. A total of 83 differentially expressed genes were identified between entire male and immunocastrated pigs, 15 between immunocastrated and surgically castrated pigs and 48 between entire male and surgically castrated pigs by RNA-sequencing of the subcutaneous adipose tissue. Comparing entire male with immunocastrated or surgically castrated pigs, upregulated genes related to extracellular matrix dynamics, and downregulated genes involved in the control of lipid and carbohydrate metabolism were determinated. Moreover, differential gene expression in general indicated a high similarity between immunocastrated and surgically castrated pigs in contrast to entire males, except for several heat shock protein genes which were upregulated in entire male and immunocastrated pigs compared with surgically castrated pigs.
2021-03-03 | GSE164391 | GEO