Leagues of their own: sexually dimorphic features of meiotic prophase I

Meiosis is a conserved cell division process that is used by sexually reproducing organisms to generate haploid gametes. Males and females produce different end products of meiosis: eggs (females) and sperm (males). In addition, these unique end products demonstrate sex-specific differences that occur throughout meiosis to produce the final genetic material that is packaged into distinct gametes with unique extracellular morphologies and nuclear sizes. These sexually dimorphic features of meiosis include the meiotic chromosome architecture, in which both the lengths of the chromosomes and the requirement for specific meiotic axis proteins being different between the sexes. Moreover, these changes likely cause sex-specific changes in the recombination landscape with the sex that has the longer chromosomes usually obtaining more crossovers. Additionally, epigenetic regulation of meiosis may contribute to sexually dimorphic recombination landscapes. Here we explore the sexually dimorphic features of both the chromosome axis and crossing over for each stage of meiotic prophase I in Mus musculus, Caenorhabditis elegans, and Arabidopsis thaliana. Furthermore, we consider how sex-specific changes in the meiotic chromosome axes and the epigenetic landscape may function together to regulate crossing over in each sex, indicating that the mechanisms controlling crossing over may be different in oogenesis and spermatogenesis.

     

Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics

Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.     

Sex chromosomes and brain gender

In birds and mammals, differences in development between the sexes arise from the differential actions of genes that are encoded on the sex chromosomes. These genes are differentially represented in the cells of males and females, and have been selected for sex-specific roles. The brain is a sexually dimorphic organ and is also shaped by sex-specific selection pressures. Genes on the sex chromosomes probably determine the gender (sexually dimorphic phenotype) of the brain in two ways: by acting on the gonads to induce sex differences in levels of gonadal secretions that have sex-specific effects on the brain, and by acting in the brain itself to differentiate XX and XY brain cells.     

Kdm6a suppresses the alternative activation of macrophages and impairs energy expenditure in obesity

Histone lysine demethylase 6a (Kdm6a) mediates the removal of repressive trimethylation from histone H3 lysine 27 (H3K27me3) to activate target gene expression. Obesity is associated with metabolic inflammation, and adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation. However, it is still unclear whether the Kdm6a pathway in ATMs regulates energy homeostasis. Here, we identified Kdm6a as a critical epigenetic switch that modulates macrophage polarisation and further disrupts energy balance. Myeloid-specific Kdm6a knockout in Kdm6a^F/Y;Lyz2-Cre mice significantly reversed the high-fat diet (HFD)-induced M1–M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity. The brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly increased in Kdm6a^F/Y;Lyz2-Cre mice. Furthermore, Kdm6a regulated the Ire1α expression in a demethylase activity-dependent manner and augmented the M2 polarisation of macrophages. Macrophage with higher Kdm6a significantly promotes adipogenesis in white adipocyte and inhibits thermogenesis in beige adipocytes. These results suggest that the Kdm6a in macrophages drives obesity and metabolic syndrome by impairing BAT activity and WAT differentiation.Subject terms: Interleukins, Epigenetics     

Sex-specific expression of a HOX gene associated with rapid morphological evolution

Animal diversity is shaped by the origin and diversification of new morphological structures. Many examples of evolutionary innovations are provided by male-specific traits involved in mating and sexual selection. The origin of new sex-specific characters requires the evolution of new regulatory interactions between sex-determining genes and genes that control spatial patterning and cell differentiation. Here, we show that sex-specific regulation of the HOX gene Sex combs reduced (Scr) is associated with the origin and evolution of the Drosophila sex comb — a novel and rapidly diversifying male-specific organ. In species that primitively lack sex combs, Scr expression shows little spatial modulation, whereas in species that have sex combs, Scr is upregulated in the presumptive sex comb region and is frequently sexually dimorphic. Phylogenetic analysis shows that sex-specific regulation of Scr has been gained and lost multiple times in Drosophila evolution and correlates with convergent origin of similar sex comb morphologies in several independent lineages. Some of these transitions occurred on microevolutionary timescales, indicating that HOX gene expression can evolve with surprising ease. This is the first example of a sex-specific regulation of a HOX gene contributing to the development and evolution of a secondary sexual trait.     

Intersexuality resulting from the interaction of sex-specific lethal mutations in Drosophila melanogaster

Male specific lethals mle, msl-1, and msl-2 interact with female specific mutations at the Sxl locus to bring about intersexuality in double mutant 2X;2A individuals. The frequency and degree to which females are sexually transformed vary among different combinations of alleles. All sexually dimorphic structures as well as the external and internal reproductive organs were found to be affected in some individuals. In general there do not appear to be substantial viability interactions between these mutants; however, under certain marginally permissive genetic and environmental conditions, lethality in double-mutant individuals did seem to be significantly less than expected. The sex-specific genes dealt with in this study were chosen because of their participation in the establishment of the level of X-chromosome function corresponding to the X/A ratio of the karyotype. The unexpected interactions of these genes leading to intersexuality are interpreted as supporting the hypothesis of a close relationship between the genetic control of sex determination and dosage compensation.     

Sex-specific gene expression in somatic tissues of Drosophila melanogaster

A hierarchy of genetic interactions controls the sexually dimorphic development of Drosophila melanogaster. The activity of a series of regulatory genes is specified, at least in part, by sex specific decisions at the level of RNA splicing. In contrast, the genes so far identified that are regulated by this hierarchy produce RNAs in one sex only. The expression of these ‘target’ genes is in some cases regulated through the decision to form a sex-specific tissue in which the genes are later expressed. In other cases, regulation requires continuous monitoring of the state of expression of the sex determination genes in a sex-nonspecific tissue.     

Post-translational histone modifications and their interaction with sex influence normal brain development and elaboration of neuropsychiatric disorders

Sex differences in the risk for and expression of various brain disorders have been known for some time. Yet, the molecular underpinnings of these sex differences as well as how sex modifies normal brain development are still poorly understood. It has recently become known that epigenetic mechanisms play an essential role in establishing and maintaining sex differences in neurodevelopment and disease susceptibility. Epigenetic mechanisms such as post-translational modifications of histones (histone PTMs) integrate various hormonal and external environmental influences to affect genomic output, and this appears to occur in a sex-dependent manner. The present review aims to highlight current understanding of the role of histone PTMs in the sexual differentiation of the brain under normal conditions and how sex-specific modulation of histone PTMs may be involved in psychiatric conditions including autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD). The role of sex chromosome genes as sex-specific histone modifiers and their importance in sexually differentiating the brain will be discussed. Further, the contribution of sex-specific histone PTM marks in the placenta in programming the sexually dimorphic developmental course of the brain and susceptibility to diseases/disorders will be reviewed. Prenatal programming may have a long-lasting effect on the adult brain and behavior but due to the interaction of histone PTMs and its modifiers with fluctuating hormone levels and external influences over the lifespan, the process remains dynamic. Although a few studies indicate an association between sex and histone PTM-related mechanisms in ASD, schizophrenia, and MDD, more research is needed to fully appreciate the interactive effects of histone PTMs and sex in the development and manifestation of these disorders. Understanding the interactions between sex and histone PTMs will advance our understanding of psychiatric disorders and potentially guide development of future treatments tailored specifically to each sex.     

Sex differences in epigenetic mechanisms may underlie risk and resilience for mental health disorders

Alterations in the epigenetic programming of sex differences in the brain may underlie sexually dimorphic neurodevelopmental disorders. Sex differences have been found in DNA methyltransferases 3a, DNA methylation patterns, MeCP2, and nuclear corepressor within the developing brain. Natural variations in these epigenetic mechanisms have profound consequences on gene expression and brain function. Exogenous or endogenous perturbations during development may impact these epigenetic processes and alter the trajectory of the developing brain and confer sexually dimorphic risk and resilience for developing a neurological or mental health disorder.     

Selective trade-offs and sex-chromosome evolution in Silene latifolia

Alleles of sexually antagonistic genes (i.e., genes with alleles affecting fitness in opposite directions in the two sexes) can avoid expression in the sex to which they are detrimental via two processes: they are subsumed into the nonrecombining, sex-determining portion of the sex chromosomes or they evolve sex-limited expression. The former is considered more likely and leads to Y-chromosome degeneration. We mapped quantitative trait loci of major effect for sexually dimorphic traits of Silene latifolia to the recombining portions of the sex chromosomes and found them to exhibit sex-specific expression, with the Y chromosome in males controlling a relatively larger proportion of genetic variance than the X in females and the average autosome. Both reproductive and ecophysiological traits map to the recombining region of the sex chromosomes. We argue that genetic correlations among traits maintain recombination and polymorphism for these genes because of balancing selection in males, whereas sex-limited expression represses detrimental alleles in females. Our data suggest that the Y chromosome of S. latifolia plays a major role in the control of key metabolic activities beyond reproductive functions.     

Modular genetic control of sexually dimorphic behaviors

Sex hormones such as estrogen and testosterone are essential for sexually dimorphic behaviors in vertebrates. However, the hormone-activated molecular mechanisms that control the development and function of the underlying neural circuits remain poorly defined. We have identified numerous sexually dimorphic gene expression patterns in the adult mouse hypothalamus and amygdala. We find that adult sex hormones regulate these expression patterns in a sex-specific, regionally restricted manner, suggesting that these genes regulate sex typical behaviors. Indeed, we find that mice with targeted disruptions of each of four of these genes (Brs3, Cckar, Irs4, Sytl4) exhibit extremely specific deficits in sex specific behaviors, with single genes controlling the pattern or extent of male sexual behavior, male aggression, maternal behavior, or female sexual behavior. Taken together, our findings demonstrate that various components of sexually dimorphic behaviors are governed by separable genetic programs.     

Gene Expression in Peripheral Immune Cells following Cardioembolic Stroke Is Sexually Dimorphic

Aims

Epidemiological studies suggest that sex has a role in the pathogenesis of cardioembolic stroke. Since stroke is a vascular disease, identifying sexually dimorphic gene expression changes in blood leukocytes can inform on sex-specific risk factors, response and outcome biology. We aimed to examine the sexually dimorphic immune response following cardioembolic stroke by studying the differential gene expression in peripheral white blood cells.

Methods and Results

Blood samples from patients with cardioembolic stroke were obtained at ≤3 hours (prior to treatment), 5 hours and 24 hours (after treatment) after stroke onset (n = 23; 69 samples) and compared with vascular risk factor controls without symptomatic vascular diseases (n = 23, 23 samples) (ANCOVA, false discovery rate p≤0.05, |fold change| ≥1.2). mRNA levels were measured on whole-genome Affymetrix microarrays. There were more up-regulated than down-regulated genes in both sexes, and females had more differentially expressed genes than males following cardioembolic stroke. Female gene expression was associated with cell death and survival, cell-cell signaling and inflammation. Male gene expression was associated with cellular assembly, organization and compromise. Immune response pathways were over represented at ≤3, 5 and 24 h after stroke in female subjects but only at 24 h in males. Neutrophil-specific genes were differentially expressed at 3, 5 and 24 h in females but only at 5 h and 24 h in males.

Conclusions

There are sexually dimorphic immune cell expression profiles following cardioembolic stroke. Future studies are needed to confirm the findings using qRT-PCR in an independent cohort, to determine how they relate to risk and outcome, and to compare to other causes of ischemic stroke.     

Testosterone Affects Neural Gene Expression Differently in Male and Female Juncos: A Role for Hormones in Mediating Sexual Dimorphism and Conflict

Despite sharing much of their genomes, males and females are often highly dimorphic, reflecting at least in part the resolution of sexual conflict in response to sexually antagonistic selection. Sexual dimorphism arises owing to sex differences in gene expression, and steroid hormones are often invoked as a proximate cause of sexual dimorphism. Experimental elevation of androgens can modify behavior, physiology, and gene expression, but knowledge of the role of hormones remains incomplete, including how the sexes differ in gene expression in response to hormones. We addressed these questions in a bird species with a long history of behavioral endocrinological and ecological study, the dark-eyed junco (Junco hyemalis), using a custom microarray. Focusing on two brain regions involved in sexually dimorphic behavior and regulation of hormone secretion, we identified 651 genes that differed in expression by sex in medial amygdala and 611 in hypothalamus. Additionally, we treated individuals of each sex with testosterone implants and identified many genes that may be related to previously identified phenotypic effects of testosterone treatment. Some of these genes relate to previously identified effects of testosterone-treatment and suggest that the multiple effects of testosterone may be mediated by modifying the expression of a small number of genes. Notably, testosterone-treatment tended to alter expression of different genes in each sex: only 4 of the 527 genes identified as significant in one sex or the other were significantly differentially expressed in both sexes. Hormonally regulated gene expression is a key mechanism underlying sexual dimorphism, and our study identifies specific genes that may mediate some of these processes.