Biology of Sex Differences最新文献

{"title":"Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats.","authors":"Bonnie H Lee, Melike Cevizci, Stephanie E Lieblich, Liisa A M Galea","doi":"10.1186/s13293-025-00694-8","DOIUrl":"10.1186/s13293-025-00694-8","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) disproportionately and uniquely affects females, and these sex differences are further exacerbated by the presence of Apolipoprotein (APOE) ε4 alleles, the top genetic risk factor for late-onset AD. To expand our understanding about how late-onset AD risk might differentially influence males and females, this study explores how APOEε4 affects hippocampal neurogenesis and microglia, key neuroplastic markers involved in AD pathogenesis, differently by sex in middle-aged rats.</p><p><strong>Methods: </strong>A rat model expressing the humanized (h) APOEε4 allele was characterized to examine markers of adult neurogenesis (neural progenitor cells and new-born neurons) and immune cells (microglia) in the dentate gyrus of the hippocampus in 13 month-old male and female rats.</p><p><strong>Results: </strong>We observed basal sex differences in neurogenesis at middle age, as wildtype male rats had greater densities of neural progenitor cells and new-born neurons in the dentate gyrus than wildtype female rats. Male hAPOEε4 rats exhibited fewer neural progenitor cells, fewer new-born neurons, and more microglia than male wildtype rats. On the other hand, female hAPOEε4 rats exhibited more new-born neurons than female wildtype rats. Interestingly, females had more microglia than males regardless of genotype. Correlations were conducted to further elucidate any sex differences in the relationships between these biomarkers. Notably, there was a significant positive correlation between neural progenitor cells and new-born neurons, and a significant negative correlation between new-born neurons and microglia, but only in male rats.</p><p><strong>Conclusion: </strong>In contrast to the clear pattern of effects of the hAPOEε4 risk factor on hippocampal neurogenesis in males, females had unaltered levels of neural progenitor cells and increased density of new-born neurons. Furthermore, relationships between neurogenesis and microglia were significantly correlated within males, and not females. This suggests that females may be presenting a compensatory response to the hAPOEε4 genotype at middle age. Collectively, these results exemplify the importance of thoroughly examining influences of sex on AD endophenotypes, as it may reveal sex-specific pathways and protective mechanisms relevant to AD.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"10"},"PeriodicalIF":4.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia.","authors":"Haolin Zheng, Akiko Mizokami, Sergio Romera-Giner, Jaime Llera-Oyola, Yosuke Yamawaki, Tomomi Sano, Eijiro Jimi, Francisco García-García, Takashi Kanematsu","doi":"10.1186/s13293-025-00686-8","DOIUrl":"10.1186/s13293-025-00686-8","url":null,"abstract":"<p><strong>Background: </strong>Significant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.</p><p><strong>Methods: </strong>Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.</p><p><strong>Results: </strong>Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.</p><p><strong>Conclusions: </strong>These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"9"},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and gender differences in the molecular etiology of Parkinson's disease: considerations for study design and data analysis.","authors":"Samantha L Schaffner, Kira N Tosefsky, Amy M Inskter, Silke Appel-Cresswell, Julia M Schulze-Hentrich","doi":"10.1186/s13293-025-00692-w","DOIUrl":"10.1186/s13293-025-00692-w","url":null,"abstract":"<p><p>Parkinson's disease (PD) is more prevalent in men than women, and presents with different clinical features in each sex. Despite widespread recognition of these differences, females are under-represented in clinical and experimental studies of PD, and much remains to be elucidated regarding the biological underpinnings of sex differences in PD. In this review, we summarize known contributors to sex differences in PD etiology across the life course, with a focus on neurological development and gene regulation. Sex differences that are established at conception and heightened during adolescence and midlife may partially embed future PD risk, due to the complex interactions between gonadal hormones, gene regulation, lifestyle factors, and aging. While the neuroprotective properties of estrogen are strongly implicated in reduced prevalence of PD in women, interactions with genotype and gender-biased lifestyle factors are incompletely understood. Consideration of sex and gender-related factors in study design, data analysis, and interpretation have the power to expedite our knowledge of the etiology of PD in men and in women, and to inform prevention and therapeutic strategies tailored to each sex.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"7"},"PeriodicalIF":4.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute stimulation of PBMCs drives switch from dopamine-induced anti- to proinflammatory phenotype of monocytes only in women.","authors":"Leonie Fleige, Silvia Capellino","doi":"10.1186/s13293-025-00689-5","DOIUrl":"10.1186/s13293-025-00689-5","url":null,"abstract":"<p><p>Several studies report an impact of the neurotransmitter dopamine (DA) on human immune cells, with effects dependent on the immune cell type addressed and their activation status. Another contributing factor appears to be sex, as sex-specific differences in the dopaminergic pathway are described in the neurological context as well as in autoimmune diseases. However, a deeper understanding of these differences in peripheral immune cells remains limited. In this study, we investigated the effects of dopaminergic stimulation on activation and cytokine secretion of peripheral blood mononuclear cells from women and men using flow cytometry, ELISA, and multiplex assays. We found a B cell-driven downregulation in cytokine secretion of monocytes exclusively from women under physiological conditions in vitro. Moreover, B cells from men showed higher dopamine receptor (DR) expression, which was shown to be further increased by sex hormones only in men. In monocytes from women, an acute inflammatory stimulus via CpG combined with dopaminergic stimulation caused a switch to a proinflammatory phenotype, which was less pronounced in men. These novel findings in sex-specific responses to dopaminergic stimulation are crucial for understanding DA's function in the healthy and activated immune system and provide evidence to treat DA-related pathologies in a sex-specific manner.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"8"},"PeriodicalIF":4.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and hand differences in haptic processing: implications for mental rotation ability.","authors":"Daniela E Aguilar Ramirez, Claudia L R Gonzalez","doi":"10.1186/s13293-025-00693-9","DOIUrl":"10.1186/s13293-025-00693-9","url":null,"abstract":"<p><p>It has been proposed that the sensorimotor system provides a foundation for the development of cognitive abilities and their hemispheric specialization. In this study, we investigated the potential relationship between haptic processing and mental rotation ability, both of which are typically lateralized to the right hemisphere. Previous research has also indicated that males tend to outperform females in both functions. The current study investigates how the sensorimotor-haptic system relates to mental rotation ability, specifically to examine the influence of hand performance (as a proxy for hemispheric specialization) and biological sex on this relationship. Seventy-five participants (n = 41 females) completed a haptic task, and the well-known mental rotation test (MRT) developed by Shepard and Metzler (Science 171:701-3, 1971). Results confirmed a positive correlation between performance on the haptic and MRT tasks. Further, males outperformed females in both tasks. However, when sex and hand performance were considered, males were better in the haptic task, but only when using their left-hand. Moreover, left-hand haptic performance was the sole predictor of MRT performance. These findings suggest that sex differences in haptic processing may contribute to the observed sex differences in mental rotation ability, supporting the view that sensorimotor processes shape cognitive function and its hemispheric lateralization.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"6"},"PeriodicalIF":4.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of chronic intermittent hypoxia on enzymatic activity in memory-associated brain regions of male and female rats.","authors":"Steve Mabry, Jessica L Bradshaw, Jennifer J Gardner, E Nicole Wilson, Janak Sunuwar, Hannah Yeung, Sharad Shrestha, J Thomas Cunningham, Rebecca L Cunningham","doi":"10.1186/s13293-025-00688-6","DOIUrl":"10.1186/s13293-025-00688-6","url":null,"abstract":"<p><strong>Background: </strong>Obstructive sleep apnea (OSA) is an intermittent hypoxia disorder associated with cognitive dysfunction, including learning and memory impairments. There is evidence that alterations in protease activity and neuronal activation are associated with cognitive dysfunction, are dependent on sex, and may be brain region-specific. However, the mechanisms mediating OSA-induced cognitive impairments are unclear. Therefore, we used a rat model of OSA, chronic intermittent hypoxia (CIH) to investigate protease activity (e.g., calpain and caspase-3) on spectrin, a cytoskeletal protein associated with neurotransmitter release, and neuronal activation (early growth response protein 1, EGR-1) in brain regions associated with learning and memory.</p><p><strong>Methods: </strong>Male and female Sprague Dawley rats were exposed to CIH or room air (normoxic) for 14 days. We quantified protease activity and cleaved spectrin products, along with EGR-1 protein expression in hippocampal subregions (CA1, CA3), cortical regions [entorhinal cortex (ETC), retrosplenial cortex (RSC), cerebellar cortex (CC)], and subcortical regions [raphe nucleus (RN), locus coeruleus (LC)] associated with learning and memory. Within each group, Pearson correlations of calpain activity, caspase-3 activity, and EGR-1 expression were performed between brain regions. Sex differences within normoxic and CIH correlations were examined.</p><p><strong>Results: </strong>CIH dysregulated calpain activity in male ETC, and female CA1 and RSC. CIH dysregulated caspase-3 activity in male RN, and female CA1 and RSC. CIH decreased calpain and caspase-3 cleavage products in male ETC. CIH decreased calpain-cleaved spectrin in male RSC but increased these products in female RSC. EGR-1 expression was decreased in male and female RN. Correlational analysis revealed CIH increased excitatory connections in males and increased inhibitory connections in females. EGR-1 expression in males shifted from negative to positive correlations.</p><p><strong>Conclusions: </strong>Overall, these data indicate CIH dysregulates protease activity and impairs neuronal function in a brain region- and sex-dependent manner. This indicates that males and females exhibit sex-specific vulnerabilities to mild OSA. These findings concur with our previous behavioral studies that demonstrated memory impairment in CIH-exposed rats.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"5"},"PeriodicalIF":4.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A meta-analysis of sex differences in neonatal rodent ultrasonic vocalizations and the implication for the preclinical maternal immune activation model.","authors":"Alison M Randell, Stephanie Salia, Lucas F Fowler, Toe Aung, David A Puts, Ashlyn Swift-Gallant","doi":"10.1186/s13293-025-00685-9","DOIUrl":"10.1186/s13293-025-00685-9","url":null,"abstract":"<p><p>As the earliest measure of social communication in rodents, ultrasonic vocalizations (USVs) in response to maternal separation are critical in preclinical research on neurodevelopmental disorders (NDDs). While sex differences in both USV production and behavioral outcomes are reported, many studies overlook sex as a biological variable in preclinical NDD models. We aimed to evaluate sex differences in USV call parameters and determine if USVs are differently impacted based on sex in the preclinical maternal immune activation (MIA) model. Results indicate that sex differences in USVs vary with developmental stage and are more pronounced in MIA offspring. Specifically, developmental stage is a moderator of sex differences in USV call duration, with control females emitting longer calls than males in early development (up to postnatal day [PND] 8), but this pattern reverses after PND8. MIA leads to a reduction in call numbers for females compared to same-sex controls in early development, with a reversal post-PND8. MIA decreased call duration and increased total call duration in males, but unlike females, developmental stage did not influence these differences. In males, MIA effects varied by species, with decreased call numbers in rats but increased call numbers in mice. MIA timing (gestational day ≤ 12.5 vs. > 12.5) did not significantly affect results. Our findings highlight the importance of considering sex, developmental timing, and species in USVs research. We discuss how analyzing USV call types and incorporating sex as a biological variable can enhance our understanding of neonatal ultrasonic communication and its translational value in NDD research.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"4"},"PeriodicalIF":4.9,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice.","authors":"Yingbin Lin, Xinqun Luo, Fangyu Wang, Huange Cai, Yuanxiang Lin, Dezhi Kang, Wenhua Fang","doi":"10.1186/s13293-025-00684-w","DOIUrl":"10.1186/s13293-025-00684-w","url":null,"abstract":"<p><strong>Background: </strong>Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer's disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood.</p><p><strong>Methods: </strong>ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice's blood glucose was also recorded.</p><p><strong>Results: </strong>Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice.</p><p><strong>Conclusions: </strong>Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"3"},"PeriodicalIF":4.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age- and sex-specific differences in myocardial sympathetic tone and left ventricular remodeling following myocardial injury.","authors":"Achi Haider, Susan Bengs, Angela Portmann, Sandro Fröhlich, Dominik Etter, Monika Maredziak, Geoffrey I Warnock, Alexander Akhmedov, Sebastian Kozerke, Claudia Keller, Fabrizio Montecucco, Bruno Weber, Linjing Mu, Ronny R Buechel, Vera Regitz-Zagrosek, Philipp A Kaufmann, Giovanni G Camici, Simon M Ametamey, Catherine Gebhard","doi":"10.1186/s13293-024-00673-5","DOIUrl":"10.1186/s13293-024-00673-5","url":null,"abstract":"<p><strong>Background: </strong>Presentations and outcomes of acute myocardial infarction (MI) differ between women and men, with the worst outcomes being reported in younger women. Mental stress induced ischemia and sympathetic activation have been suggested to play a prominent role in the pathogenesis of MI in younger women, however, the impact of sex hormones on these parameters remains unknown.</p><p><strong>Methods: </strong>The effect of sex hormones and age on myocardial infarct size and myocardial sympathetic activity (MSA) was assessed in male and female, as well as young (4-6 months) and aged (20-22 months) FVB/N mice (n = 106, 60 gonadectomized and 46 sham-operated animals) who underwent in vivo [¹¹C]meta-hydroxyephedrine ([¹¹C]mHED) positron emission tomography (PET) and cardiac magnetic resonance (CMR) imaging 24 h after a 30 min myocardial ischemic injury.</p><p><strong>Results: </strong>MSA and catecholamine levels following myocardial injury were highest in young males (p = 0.008 and p = 0.043 vs. young females, respectively) and were reduced by orchiectomy. Accordingly, testosterone serum levels correlated positively with MSA (r = 0.66, p < 0.001). Males had a larger average infarct size and lower left ventricular contractility following myocardial injury than females (p < 0.05 vs. females). These sex differences were no longer evident in gonadectomized animals (p = NS vs. females). In female animals, estrogen depletion did not affect MSA (ovariectomy effect, p = 0.892). Female animals showed an age-dependent increase in MSA (p = 0.011), which was absent in males.</p><p><strong>Conclusion: </strong>Testosterone associates with an increase in sympathetic tone, contributing to adverse cardiac remodeling following MI. Conversely, females maintain sympathetic integrity, independent of sex hormones. Our results suggest a biological advantage of female sex in post MI recovery. Further research is warranted to confirm these findings in humans.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"2"},"PeriodicalIF":4.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KDM6A facilitates Xist upregulation at the onset of X inactivation.","authors":"Josephine Lin, Jinli Zhang, Li Ma, He Fang, Rui Ma, Camille Groneck, Galina N Filippova, Xinxian Deng, Chizuru Kinoshita, Jessica E Young, Wenxiu Ma, Christine M Disteche, Joel B Berletch","doi":"10.1186/s13293-024-00683-3","DOIUrl":"10.1186/s13293-024-00683-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;X chromosome inactivation (XCI) is a female-specific process in which one X chromosome is silenced to balance X-linked gene expression between the sexes. XCI is initiated in early development by upregulation of the lncRNA Xist on the future inactive X (Xi). A subset of X-linked genes escape silencing and thus have higher expression in females, suggesting female-specific functions. One of these genes is the highly conserved gene Kdm6a, which encodes a histone demethylase that removes methyl groups at H3K27 to facilitate gene expression. KDM6A mutations have been implicated in congenital disorders such as Kabuki Syndrome, as well as in sex differences in development and cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Kdm6a was knocked out (KO) using CRISPR/Cas9 gene editing in hybrid female mouse embryonic stem (ES) cells derived either from a 129 × Mus castaneus (cast) cross or a BL6 x cast cross. In one of the lines a transcriptional stop signal inserted in Tsix results in completely skewed X silencing upon differentiation. The effects of both homozygous and heterozygous Kdm6a KO on Xist expression during the onset of XCI were measured by RT-PCR and RNA-FISH. Changes in gene expression and in H3K27me3 enrichment were investigated using allele-specific RNA-seq and Cut&Run, respectively. KDM6A binding to the Xist gene was characterized by Cut&Run.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We observed impaired upregulation of Xist and reduced coating of the Xi during early stages of differentiation in Kdm6a KO cells, both homozygous and heterozygous, suggesting a threshold effect of KDM6A. This was associated with aberrant overexpression of genes from the Xi after differentiation, indicating loss of X inactivation potency. Consistent with KDM6A having a direct role in Xist regulation, we found that the histone demethylase binds to the Xist promoter and KO cells show an increase in H3K27me3 at Xist, consistent with reduced expression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;These results reveal a novel female-specific role for the X-linked histone demethylase, KDM6A in the initiation of XCI through histone demethylase-dependent activation of Xist during early differentiation. X chromosome inactivation is a female-specific mechanism that evolved to balance sex-linked gene dosage between females (XX) and males (XY) by silencing one X chromosome in females. X inactivation begins with the upregulation of the long noncoding RNA Xist on the future inactive X chromosome. While most genes become silenced on the inactive X chromosome some genes escape inactivation and thus have higher expression in females compared to males, suggesting that escape genes may have female-specific functions. One such gene encodes the histone demethylase KDM6A which function is to turn on gene expression by removing repressive histone modifications. In this study, we investigated the role of KDM6A in the regulation of Xist expression during the onset of X inactivation. ","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"1"},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}