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Nature Reviews. Disease Primers Oct 2023Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways... (Review)
Review
Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways depending on whether the disease is non-muscle invasive or muscle invasive. The mutational burden is higher in muscle-invasive than in non-muscle-invasive disease. Commonly mutated genes include TERT, FGFR3, TP53, PIK3CA, STAG2 and genes involved in chromatin modification. Subtyping of both forms of bladder cancer is likely to change considerably with the advent of single-cell analysis methods. Early detection signifies a better disease prognosis; thus, minimally invasive diagnostic options are needed to improve patient outcomes. Urine-based tests are available for disease diagnosis and surveillance, and analysis of blood-based cell-free DNA is a promising tool for the detection of minimal residual disease and metastatic relapse. Transurethral resection is the cornerstone treatment for non-muscle-invasive bladder cancer and intravesical therapy can further improve oncological outcomes. For muscle-invasive bladder cancer, radical cystectomy with neoadjuvant chemotherapy is the standard of care with evidence supporting trimodality therapy. Immune-checkpoint inhibitors have demonstrated benefit in non-muscle-invasive, muscle-invasive and metastatic bladder cancer. Effective management requires a multidisciplinary approach that considers patient characteristics and molecular disease characteristics.
Topics: Humans; Female; Male; Treatment Outcome; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms; Urinary Bladder; Prognosis
PubMed: 37884563
DOI: 10.1038/s41572-023-00468-9 -
Cell Feb 2024Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist...
Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
Topics: Animals; Female; Humans; Male; Mice; Autoantibodies; Autoimmune Diseases; Autoimmunity; Ribonucleoproteins; RNA, Long Noncoding; X Chromosome; X Chromosome Inactivation; Sex Characteristics
PubMed: 38306984
DOI: 10.1016/j.cell.2023.12.037 -
Nature Jul 2023Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively...
Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRAS and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8 T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
Topics: Animals; Female; Humans; Male; Mice; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Disease Models, Animal; Histone Demethylases; Mice, Transgenic; Minor Histocompatibility Antigens; Sex Characteristics; Up-Regulation
PubMed: 37344599
DOI: 10.1038/s41586-023-06254-7 -
Nature Medicine Oct 2023Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during...
Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3 p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P < 10; advanced fibrosis/hepatocellular carcinoma, P = 0.034) and in the general population (P < 10 for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3 expression was higher in women than in men (P = 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3 was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3 enhancer and demonstrated via CRISPR-Cas9 genome editing that this sequence drives PNPLA3 p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3 p.I148M variant contributes to FLD in women.
Topics: Animals; Female; Humans; Male; Mice; Acyltransferases; Carcinoma, Hepatocellular; Fibrosis; Genetic Predisposition to Disease; Liver; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Phospholipases A2, Calcium-Independent; Receptors, Estrogen
PubMed: 37749332
DOI: 10.1038/s41591-023-02553-8 -
Cell Proliferation Oct 2023Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono-ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the...
Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono-ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the well-recognized mechanisms for Polycomb repressive complex 1 (PRC1)-mediated transcription repression. Unexpectedly, the specific H2AK119 deubiquitylation complex composed by additional sex comb-like proteins and BAP1 has also been genetically characterized as Polycomb repressive deubiquitnase (PR-DUB) for unclear reasons. However, it remains a mystery whether and how PR-DUB deficiency affects chromatin states and cell fates through impaired PcG silencing. Here through a careful epigenomic analysis, we demonstrate that a bulk of H2AK119ub1 is diffusely distributed away from promoter regions and their enrichment is positively correlated with PRC1 occupancy. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), a pervasive gain of H2AK119ub1 is coincident with increased PRC1 sampling at chromatin. Accordingly, PRC1 is significantly lost from a subset of highly occupied promoters, leading to impaired silencing of associated genes before and after lineage differentiation of Asxl2-null ESCs. Therefore, our study highlights the importance of genome-wide H2AK119ub1 restriction by PR-DUB in safeguarding robust PRC1 deposition and its roles in developmental regulation.
Topics: Animals; Mice; Polycomb-Group Proteins; Histones; Chromatin; Polycomb Repressive Complex 1; Ubiquitination; Drosophila Proteins
PubMed: 36959757
DOI: 10.1111/cpr.13457 -
Trends in Neurosciences Jan 2024Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but it continues throughout... (Review)
Review
Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but it continues throughout life, as a result of the interaction of three major factors: gonadal hormones, sex chromosomes, and the environment. These factors are thought to act, in part, via epigenetic mechanisms which control chromatin and transcriptional states in brain cells. In this review, we discuss evidence that epigenetic mechanisms underlie sex-specific neurobehavioral changes during critical organizational periods, across the estrous cycle, and in response to diverse environments throughout life. We further identify future directions for the field that will provide novel mechanistic insights into brain sex differences, inform brain disease treatments and women's brain health in particular, and apply to people across genders.
Topics: Humans; Male; Female; Sex Characteristics; Brain; Epigenesis, Genetic; Brain Diseases; Sex Differentiation
PubMed: 37968206
DOI: 10.1016/j.tins.2023.09.007 -
ELife Jul 2023Sex-specific splicing is an essential process that regulates sex determination and drives sexual dimorphism. Yet, how early in development widespread sex-specific...
Sex-specific splicing is an essential process that regulates sex determination and drives sexual dimorphism. Yet, how early in development widespread sex-specific transcript diversity occurs was unknown because it had yet to be studied at the genome-wide level. We use the powerful model to show that widespread sex-specific transcript diversity occurs early in development, concurrent with zygotic genome activation. We also present a new pipeline called time2Splice to quantify changes in alternative splicing over time. Furthermore, we determine that one of the consequences of losing an essential maternally deposited pioneer factor called CLAMP (chromatin-linked adapter for MSL proteins) is altered sex-specific splicing of genes involved in diverse biological processes that drive development. Overall, we show that sex-specific differences in transcript diversity exist even at the earliest stages of development..
Topics: Animals; Male; Female; Drosophila; Drosophila melanogaster; Drosophila Proteins; Embryonic Development; Genome; Alternative Splicing
PubMed: 37466240
DOI: 10.7554/eLife.87865 -
BioRxiv : the Preprint Server For... Dec 2023Sex differences are found in brain structure and function across species, and across brain disorders in humans. The major source of brain sex differences is differential...
Sex differences are found in brain structure and function across species, and across brain disorders in humans. The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan. Specifically, ovarian hormones oestrogens and progesterone are known to dynamically change structure and function of the adult female brain, having a major impact on psychiatric risk. However, due to limited molecular studies in female rodents, very little is still known about molecular drivers of female-specific brain and behavioural plasticity. Here we show that overexpressing Egr1, a candidate oestrous cycle-dependent transcription factor, induces sex-specific changes in ventral hippocampal neuronal chromatin, gene expression, and synaptic plasticity, along with hippocampus-dependent behaviours. Importantly, Egr1 overexpression mimics the high-oestrogenic phase of the oestrous cycle, and affects behaviours in ovarian hormone-depleted females but not in males. We demonstrate that Egr1 opens neuronal chromatin directly across the sexes, although with limited genomic overlap. Our study not only reveals the first sex-specific chromatin regulator in the brain, but also provides functional evidence that this sex-specific gene regulation drives neuronal gene expression, synaptic plasticity, and anxiety- and depression-related behaviour. Our study exemplifies an innovative sex-based approach to studying neuronal gene regulation in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.
PubMed: 38187614
DOI: 10.1101/2023.12.20.572697 -
Cell Death & Disease Aug 2023Gonadal sex determination and differentiation are controlled by somatic support cells of testes (Sertoli cells) and ovaries (granulosa cells). In testes, the epigenetic...
Gonadal sex determination and differentiation are controlled by somatic support cells of testes (Sertoli cells) and ovaries (granulosa cells). In testes, the epigenetic mechanism that maintains chromatin states responsible for suppressing female sexual differentiation remains unclear. Here, we show that Polycomb repressive complex 1 (PRC1) suppresses a female gene regulatory network in postnatal Sertoli cells. We genetically disrupted PRC1 function in embryonic Sertoli cells after sex determination, and we found that PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed specific genes required for granulosa cells, thereby inactivating the female gene regulatory network. Chromatin regions associated with female-specific genes were marked by Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, this study identifies a critical Polycomb-based mechanism that suppresses ovarian differentiation and maintains Sertoli cell fate in adult testes.
Topics: Female; Male; Humans; Polycomb Repressive Complex 1; Histones; Testis; Gene Regulatory Networks; Polycomb Repressive Complex 2; Chromatin; Polycomb-Group Proteins; Cell Differentiation
PubMed: 37542070
DOI: 10.1038/s41419-023-05996-6 -
Human Genomics Oct 2023Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown....
BACKGROUND
Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.
METHODS
We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.
RESULTS
We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.
CONCLUSIONS
A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
Topics: Humans; Male; Infant, Newborn; Female; Down Syndrome; Epigenomics; DNA Methylation; Epigenesis, Genetic; Heart Defects, Congenital; CpG Islands; Chromatin
PubMed: 37803336
DOI: 10.1186/s40246-023-00540-1