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Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria.Biology of Sex Differences Jan 2014Several autoimmune and neurological diseases exhibit a sex bias, but discerning the causes and mechanisms of these biases has been challenging. Sex differences begin to...
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.
PubMed: 24422881
DOI: 10.1186/2042-6410-5-2 -
FASEB Journal : Official Publication of... Sep 2022Meiosis has a principal role in sexual reproduction to generate haploid gametes in both sexes. During meiosis, the cell nucleus hosts a dynamic environment where some...
Meiosis has a principal role in sexual reproduction to generate haploid gametes in both sexes. During meiosis, the cell nucleus hosts a dynamic environment where some genes are transcriptionally activated, and some are inactivated at the same time. This becomes possible through subnuclear compartmentalization. The sex body, sequestering X and Y chromosomes during male meiosis and creating an environment for the meiotic sex chromosome inactivation (MSCI) is one of the best known and studied subnuclear compartments. Herein, we show that MRNIP forms droplet-like accumulations that fuse together to create a distinct subnuclear compartment that partially overlaps with the sex body chromatin during diplotene. We demonstrate that Mrnip spermatocytes have impaired DNA double-strand break (DSB) repair, they display reduced sex body formation and defective MSCI. We show that Mrnip undergoes critical meiocyte loss at the diplotene stage. Furthermore, we determine that DNA DSBs (induced by SPO11) and synapsis initiation (facilitated by SYCP1) precede Mrnip expression in testes. Altogether, our findings indicate that in addition to an emerging role in DNA DSB repair, MRNIP has an essential function in spermatogenesis during meiosis I by forming drop-like accumulations interacting with the sex body.
Topics: Animals; Chromatin; Female; Fertility; Male; Meiosis; Mice; Spermatocytes; Spermatogenesis; Y Chromosome
PubMed: 35920200
DOI: 10.1096/fj.202101168RR -
Genome Research May 2012Sex chromosome inactivation is essential epigenetic programming in male germ cells. However, it remains largely unclear how epigenetic silencing of sex chromosomes...
Sex chromosome inactivation is essential epigenetic programming in male germ cells. However, it remains largely unclear how epigenetic silencing of sex chromosomes impacts the evolution of the mammalian genome. Here we demonstrate that male sex chromosome inactivation is highly conserved between humans and mice and has an impact on the genetic evolution of human sex chromosomes. We show that, in humans, sex chromosome inactivation established during meiosis is maintained into spermatids with the silent compartment postmeiotic sex chromatin (PMSC). Human PMSC is illuminated with epigenetic modifications such as trimethylated lysine 9 of histone H3 and heterochromatin proteins CBX1 and CBX3, which implicate a conserved mechanism underlying the maintenance of sex chromosome inactivation in mammals. Furthermore, our analyses suggest that male sex chromosome inactivation has impacted multiple aspects of the evolutionary history of mammalian sex chromosomes: amplification of copy number, retrotranspositions, acquisition of de novo genes, and acquisition of different expression profiles. Most strikingly, profiles of escape genes from postmeiotic silencing diverge significantly between humans and mice. Escape genes exhibit higher rates of amino acid changes compared with non-escape genes, suggesting that they are beneficial for reproductive fitness and may allow mammals to cope with conserved postmeiotic silencing during the evolutionary past. Taken together, we propose that the epigenetic silencing mechanism impacts the genetic evolution of sex chromosomes and contributed to speciation and reproductive diversity in mammals.
Topics: Animals; Chromatin; Chromobox Protein Homolog 5; Chromosomes, Human, Y; Epigenesis, Genetic; Evolution, Molecular; Gene Dosage; Gene Expression Profiling; Genes, X-Linked; Humans; Male; Meiosis; Mice; Oligonucleotide Array Sequence Analysis; Spermatogenesis; Spermatogonia; Transcription, Genetic
PubMed: 22375025
DOI: 10.1101/gr.135046.111 -
Nucleic Acids Research Apr 2022In many eukaryotes, such as dioicous mosses and many algae, sex is determined by UV sex chromosomes and is expressed during the haploid phase of the life cycle. In these...
In many eukaryotes, such as dioicous mosses and many algae, sex is determined by UV sex chromosomes and is expressed during the haploid phase of the life cycle. In these species, the male and female developmental programs are initiated by the presence of the U- or V-specific regions of the sex chromosomes but, as in XY and ZW systems, sexual differentiation is largely driven by autosomal sex-biased gene expression. The mechanisms underlying the regulation of sex-biased expression of genes during sexual differentiation remain elusive. Here, we investigated the extent and nature of epigenomic changes associated with UV sexual differentiation in the brown alga Ectocarpus, a model UV system. Six histone modifications were quantified in near-isogenic lines, leading to the identification of 16 chromatin signatures across the genome. Chromatin signatures correlated with levels of gene expression and histone PTMs changes in males versus females occurred preferentially at genes involved in sex-specific pathways. Despite the absence of chromosome scale dosage compensation and the fact that UV sex chromosomes recombine across most of their length, the chromatin landscape of these chromosomes was remarkably different to that of autosomes. Hotspots of evolutionary young genes in the pseudoautosomal regions appear to drive the exceptional chromatin features of UV sex chromosomes.
Topics: Chromatin; Dosage Compensation, Genetic; Evolution, Molecular; Haploidy; Phaeophyceae; Sex Chromosomes
PubMed: 35253891
DOI: 10.1093/nar/gkac145 -
Developmental Biology Feb 2019Cis-regulatory elements are critical for the precise spatiotemporal regulation of genes during development. However, identifying functional regulatory sites that drive...
Cis-regulatory elements are critical for the precise spatiotemporal regulation of genes during development. However, identifying functional regulatory sites that drive cell differentiation in vivo has been complicated by the high numbers of cells required for whole-genome epigenetic assays. Here, we identified putative regulatory elements during sex determination by performing ATAC-seq and ChIP-seq for H3K27ac in purified XX and XY gonadal supporting cells before and after sex determination in mice. We show that XX and XY supporting cells initiate sex determination with similar chromatin landscapes and acquire sex-specific regulatory elements as they commit to the male or female fate. To validate our approach, we identified a functional gonad-specific enhancer downstream of Bmp2, an ovary-promoting gene. This work increases our understanding of the complex regulatory network underlying mammalian sex determination and provides a powerful resource for identifying non-coding regulatory elements that could harbor mutations that lead to Disorders of Sexual Development.
Topics: Acetylation; Animals; Chromatin; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gonads; High-Throughput Nucleotide Sequencing; Histones; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Regulatory Sequences, Nucleic Acid; Sex Determination Processes
PubMed: 30594505
DOI: 10.1016/j.ydbio.2018.12.023 -
BMC Biology Apr 2023The protozoan malaria parasite Plasmodium falciparum has a complex life cycle during which it needs to differentiate into multiple morphologically distinct life forms. A...
BACKGROUND
The protozoan malaria parasite Plasmodium falciparum has a complex life cycle during which it needs to differentiate into multiple morphologically distinct life forms. A key process for transmission of the disease is the development of male and female gametocytes in the human blood, yet the mechanisms determining sexual dimorphism in these haploid, genetically identical sexual precursor cells remain largely unknown. To understand the epigenetic program underlying the differentiation of male and female gametocytes, we separated the two sexual forms by flow cytometry and performed RNAseq as well as comprehensive ChIPseq profiling of several histone variants and modifications.
RESULTS
We show that in female gametocytes the chromatin landscape is globally remodelled with respect to genome-wide patterns and combinatorial usage of histone variants and histone modifications. We identified sex specific differences in heterochromatin distribution, implicating exported proteins and ncRNAs in sex determination. Specifically in female gametocytes, the histone variants H2A.Z/H2B.Z were highly enriched in H3K9me3-associated heterochromatin. H3K27ac occupancy correlated with stage-specific gene expression, but in contrast to asexual parasites this was unlinked to H3K4me3 co-occupancy at promoters in female gametocytes.
CONCLUSIONS
Collectively, we defined novel combinatorial chromatin states differentially organising the genome in gametocytes and asexual parasites and unravelled fundamental, sex-specific differences in the epigenetic code. Our chromatin maps represent an important resource for future understanding of the mechanisms driving sexual differentiation in P. falciparum.
Topics: Animals; Male; Female; Humans; Plasmodium falciparum; Histones; Heterochromatin; Chromatin Assembly and Disassembly; Sex Differentiation; Malaria, Falciparum; Chromatin; Parasites; Protozoan Proteins
PubMed: 37013531
DOI: 10.1186/s12915-023-01568-4 -
Mucosal Immunology Oct 2023This study investigates sex-associated systemic innate immune differences by examining bone marrow-derived dendritic cells (BMDCs). BMDC grown from 7-day-old mice show...
This study investigates sex-associated systemic innate immune differences by examining bone marrow-derived dendritic cells (BMDCs). BMDC grown from 7-day-old mice show enhanced type-I interferon (IFN) signaling in female compared to male BMDC. Upon respiratory syncytial virus (RSV) infection of 7-day-old mice, a significantly altered phenotype of BMDC at 4 weeks post-infection is observed in a sex-dependent manner. The alterations include heightened Ifnb/ interleukin (Il12a) and enhanced IFNAR1+ expression in BMDC from early-life RSV-infected female mice that leads to increased IFN-γ production by T cells. Phenotypic differences were verified upon pulmonary sensitization whereby EL-RSV male-derived BMDC promoted enhanced T helper 2/17 responses and exacerbated disease upon RSV infection while EL-RSV/F BMDC sensitization was relatively protective. Assay for transposase-accessible chromatin using sequencing analysis (ATAC-seq) demonstrated that EL-RSV/F BMDC had enhanced chromatin accessibility near type-I immune genes with JUN, STAT1/2, and IRF1/8 transcription factors predicted to have binding sites in accessible regions. Importantly, ATAC-seq of human cord blood-derived monocytes displayed a similar sex-associated chromatin landscape with female-derived monocytes having more accessibility in type-I immune genes. These studies enhance our understanding of sex-associated differences in innate immunity by epigenetically controlled transcriptional programs amplified by early-life infection in females via type-I immunity.
Topics: Male; Mice; Female; Humans; Animals; Chromatin Assembly and Disassembly; Respiratory Syncytial Virus Infections; Immunity, Innate; Lung; Interferon Type I; Chromatin
PubMed: 37302711
DOI: 10.1016/j.mucimm.2023.06.002 -
Cancer Cytopathology Jan 2022Gynecologic sex cord-stromal tumors (SCSTs) arise from sex cords of the embryonic gonad and may display malignant behavior. We describe the cytomorphologic features of...
BACKGROUND
Gynecologic sex cord-stromal tumors (SCSTs) arise from sex cords of the embryonic gonad and may display malignant behavior. We describe the cytomorphologic features of SCSTs in females, including adult and juvenile granulosa cell tumors (AGCTs and JGCTs), Sertoli-Leydig cell tumors (SLCTs), and steroid cell tumors (SCTs).
METHODS
We retrieved available cytology slides from females with a histologic diagnosis of sex cord-stromal tumor between 2009 and 2020 from institutional archives and reviewed their cytoarchitectural features.
RESULTS
There were 25, 2, 2, and 1 cytology specimens from 19, 2, 2, and 1 patients (aged 7-90 years, median 57 years) with AGCT, JGCT, SLCT, and SCT, respectively. Features common to all SCSTs included 3-dimensional groups, rosettes, rare papillary fragments, abundant single cells and naked nuclei. Rosettes and a streaming appearance of cell groups were only seen in AGCTs, which also rarely featured eosinophilic hyaline globules and metachromatic stroma. AGCTs exhibited high nuclear:cytoplasmic (N:C) ratios, with mild nuclear pleomorphism, uniform nuclei with finely granular chromatin, nuclear grooves and small nucleoli; in contrast, other SCSTs lacked rosettes and nuclear grooves and had generally lower N:C ratios, greater nuclear pleomorphism, coarse chromatin and more abundant cytoplasm. Mitotic figures, necrosis, and inflammation were rarely identified.
CONCLUSIONS
AGCTs show cytomorphologic features that are distinct from those of other SCSTs. Careful evaluation of the cytological features and ancillary studies (eg, immunochemistry for FOXL2, inhibin and calretinin, or sequencing for FOXL2 mutations) can aid in the accurate diagnosis of these tumors.
Topics: Adult; Chromatin; Female; Granulosa Cell Tumor; Humans; Mutation; Ovarian Neoplasms; Sex Cord-Gonadal Stromal Tumors
PubMed: 34411449
DOI: 10.1002/cncy.22502 -
Biology of Sex Differences Dec 2022Monopterus albus is a hermaphroditic and economically farmed fish that undergoes sex reversal from ovary to testis via ovotestis during gonadal development. The...
Integrated chromatin accessibility and DNA methylation analysis to reveal the critical epigenetic modification and regulatory mechanism in gonadal differentiation of the sequentially hermaphroditic fish, Monopterus albus.
BACKGROUND
Monopterus albus is a hermaphroditic and economically farmed fish that undergoes sex reversal from ovary to testis via ovotestis during gonadal development. The epigenetic changes that are associated with gonadal development in this species remain unclear.
METHODS
We produced DNA methylome, transcriptome, and chromatin accessibility maps of the key stages of gonad development: ovary, ovotestis, and testis. The expression of the key candidate genes was detected using qRT-PCR and in situ hybridization and the methylation levels were analysed using bisulphite sequencing PCR. Promoter activity and regulation were assessed using dual-luciferase reporter assays.
RESULTS
Gonadal development exhibits highly dynamic transcriptomic, DNA methylation, and chromatin accessibility changes. We found that DNA methylation status, especially of the transcription start site, was significantly negatively correlated with gene expression while chromatin accessibility exhibited no correlation with gene expression during gonadal development. The epigenetic signatures revealed many novel regulatory elements and genes involved in sex reversal, which were validated. DNA methylation detection and site mutation of plastin-2 promoter, as a candidate gene, revealed that DNA methylation could impact the binding of transcription factor dmrt1 and foxl2 through methylation and demethylation to regulate plastin-2 expression during gonadal development.
CONCLUSIONS
These data provide novel insights into epigenetic modification and help elucidate the potential molecular mechanism by which dynamic modification of DNA methylation plays a crucial role in gonadal development.
Topics: Male; Animals; Female; DNA Methylation; Chromatin; Gonads; Ovary; Epigenesis, Genetic
PubMed: 36539889
DOI: 10.1186/s13293-022-00484-6 -
Chromosoma Apr 2007Sex chromosomes in different organisms are studied as model systems for chromatin regulation of transcription and epigenetics. Similar to the female X in mammals, the... (Review)
Review
Sex chromosomes in different organisms are studied as model systems for chromatin regulation of transcription and epigenetics. Similar to the female X in mammals, the male X chromosome in Drosophila is involved in the process of dosage compensation. However, in contrast to one of the mammalian female X chromosomes undergoing inactivation, the Drosophila male X is transcriptionally upregulated by approximately twofold. The Drosophila male X is a remarkable example for a specialized, transcriptionally hyperactive chromatin domain that facilitates the study of chromatin regulation in the context of transcription, nuclear architecture, and chromatin remodeling. In addition, the rich phenomenology of dosage compensation in Drosophila provides an opportunity to explore the complexities of gene regulation through epigenetic chromatin configurations, histone modifications, and noncoding RNAs. Male-specific lethal (MSL) factors constitute the MSL complex or dosage compensation complex and are important for transcription regulation of X-linked genes. Recent biochemical studies have identified a number of interesting factors that associate with the MSL complex including components of the nuclear pore complex and exosome subunits. Furthermore, global analysis of MSL complex binding showed that MSL complexes are enriched on genes with preferential binding to 3' end of genes. Taken together, these findings suggest a role of the MSL complex in transcription elongation, RNA processing, and/or nuclear organization.
Topics: Animals; Chromatin; Chromosomal Proteins, Non-Histone; DNA Helicases; DNA-Binding Proteins; Dosage Compensation, Genetic; Drosophila; Drosophila Proteins; Epigenesis, Genetic; Gene Expression Regulation; Histone Acetyltransferases; Male; Models, Genetic; Multiprotein Complexes; Nuclear Proteins; Protein Binding; Protein Structure, Tertiary; Transcription Factors; X Chromosome
PubMed: 17124606
DOI: 10.1007/s00412-006-0089-x