Project description:Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted whole genome bisulfite sequencing (WGBS) as well as RNA-seq on liver samples from mice with different combinations of sex phenotype and sex-chromosome complement. We compared groups of animals with different sex phenotypes, but the same genetic sexes, and vice versa, same sex phenotypes, but different sex-chromosome complements. We also compared sex-biased DNA methylation in mouse and human livers. Our data show that sex phenotype, X-chromosome dosage, and the presence of Y chromosome shape the differences in DNA methylation between males and females. We also demonstrate that sex bias in autosomal methylation is associated with sex bias in gene expression, whereas X-chromosome dosage-dependent methylation differences are not, as expected for a dosage-compensation mechanism. Furthermore, we find partial conservation between the repertoires of mouse and human genes that are associated with sex-biased methylation, an indication that gene function is likely to be an important factor in this phenomenon.
Project description:Childhood and cumulative exposure to trauma increases an individual's lifetime risk for psychiatric and stress-related disorders. This study evaluates DNA methylation in whole blood from African American participants, with the goal of identifying associaitons between peripheral DNA methylation and psychiatric symptoms. DNA methylation was assessed in whole blood from participants of the Grady Trauma Project. Blood was collected in EDTA vacuum tubes prior to extraction. DNA methylation was interrogated for each sample using the HumanMethylation450 BeadChip (Illumina).
Project description:Childhood and cumulative exposure to trauma increases an individual's lifetime risk for psychiatric and stress-related disorders. This study evaluates DNA methylation in whole blood, with the goal of identifying associaitons between peripheral DNA methylation and psychiatric symptoms.
Project description:Cord blood DNA methylation is associated with numerous health outcomes and environmental exposures. Whole cord blood DNA reflects all nucleated blood cell types, while centrifuging whole blood separates red blood cells by generating a white blood cell buffy coat. Both sample types are used in DNA methylation studies. Cell types have unique methylation patterns and processing can impact cell distributions, which may influence comparability. To evaluate differences in cell composition and DNA methylation between buffy coat and whole cord blood samples, cord blood DNA methylation was measured with the Infinium EPIC BeadChip (Illumina) in 8 individuals, each contributing buffy coat and whole blood samples.
Project description:Childhood and cumulative exposure to trauma increases an individual's lifetime risk for psychiatric and stress-related disorders. This study evaluates DNA methylation in whole blood from African American participants, with the goal of identifying associaitons between peripheral DNA methylation and psychiatric symptoms.
Project description:Gender differences in the prevalence of psychiatric disorders are well documented in epidemiological studies. Exposure to stress during gestation impacts differentially between females and males. Environmental or biological factors can alter DNA methylation and affect the development of neurodevelopmental diseases. In this study, we explored gender-specific DNA methylation in regarding their potential connection to psychiatric outcomes. We assessed the methylation of cord blood of 39 females and 32 males born at term and with appropriate weight at birth. Mothers between 18 and 48 years of age (median: 28 years) were interviewed to gather information about environmental factors (gestational exposure) that can potentially interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. After exclusion of XYS probes, there were 2,332 differentially methylated CpG sites (DMS) between sexes, with an overlap of 890 (38%) CpG sites with an a cohort submitted to gestational stress exposition. Using externals datasets, we found that the DMSs were enriched within brain modules of co-methylated CpGs during gestation and were also differentially methylated in the brain comparing boys and girls during brain development. Genes associated to the DMSs were enriched for neurodevelopmental disorders. Accordingly, we described an enrichment of the DMSs among the differentially methylated CpG sites in brain tissue between schizophrenics and controls. Here, we suggest that gender changes methylation in the autosomes working as a primary driver to stress exposition which potentially contributes for gender differences found in psychiatric outcomes.
Project description:Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain. To investigate this, we interrogated genome-wide DNA methylation in postmortem hippocampus from 32 BD-I patients and 32 age-, sex-, and race-matched non-psychiatric controls from the NIMH Human Brain Collection Core.
Project description:Background There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established. Methods In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n=22-24 per group/region). Findings We found over 3,000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in Astrocytes, Drd3+MSNs and Oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS). Interpretation Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross- disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS.
Project description:The impact of STAT5 on liver DNA methylation was assessed by performing RRBS analysis on male and female mouse liver with a hepatocyte-specific loss of STAT5a and STAT5b. Extensive changes in CpG-methylation were seen in STAT5-deficient liver, where sex differences were abolished at 88% of ~1,500 sex-differentially methylated regions, largely due to increased DNA methylation upon STAT5 loss. STAT5-dependent CpG-hypomethylation was rarely found at proximal promoters of STAT5-dependent genes. Rather, STAT5 primarily regulated the methylation of distal enhancers, where STAT5 deficiency induced widespread hypermethylation at genomic regions enriched for accessible chromatin, enhancer histone marks (H3K4me1, H3K27ac), STAT5 binding, and DNA motifs for STAT5 and other transcription factors implicated in liver sex differences. Thus, the sex-dependent binding of STAT5 to liver chromatin is closely linked to the sex-dependent demethylation of distal regulatory elements linked to STAT5-dependent genes important for liver sex bias.
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.