Postmortem tissue biomarkers of menopausal transition.

The menopausal transition (MT) is associated with an increased risk for many disorders including neurological and mental disorders. Brain imaging studies in living humans show changes in brain metabolism and structure that may contribute to the MT-associated brain disease risk. Although deficits in ovarian hormones have been implicated, cellular and molecular studies of the brain undergoing MT are currently lacking, mostly due to a difficulty in studying MT in postmortem human brain.

Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour.

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.

Epigenetic mechanisms underlying sex differences in the brain and behavior.

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.

Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine.

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here, we reveal molecular substrates in the reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine. We find shared involvement of X chromosome inactivation-related and estrogen signaling-related gene regulation in enhanced conditioning responses following early-life stress and during the low-estrogenic state in females.

Hippocampus-based behavioral, structural, and molecular dynamics across the estrous cycle.

The activity of neurons in the rodent hippocampus contributes to diverse behaviors, with the activity of ventral hippocampal neurons affecting behaviors related to anxiety and emotion regulation, and the activity of dorsal hippocampal neurons affecting performance in learning- and memory-related tasks. Hippocampal cells also express receptors for ovarian hormones, estrogen and progesterone, and are therefore affected by physiological fluctuations of those hormones that occur over the rodent estrous cycle. In this review, we discuss the effects of cycling ovarian hormones on hippocampal physiology.

Why the estrous cycle matters for neuroscience.

Background: Ovarian hormone fluctuations over the rodent estrous cycle and the human menstrual cycle are known to significantly impact brain physiology and disease risk, yet this variable is largely ignored in preclinical neuroscience research, clinical studies, and psychiatric practice.

Methods: To assess the importance of the estrous cycle information for the analysis of sex differences in neuroscience research, we re-analyzed our previously published data with or without the estrous cycle information, giving a side-by-side comparison of the analyses of behavior, brain structure, gene expression, and 3D genome organization in female and male mice. We also examined and compared the variance of female and male groups across all neurobehavioral measures.

BET-ting on histone proteomics in schizophrenia.

In a recent study, Farrelly, Zheng, and colleagues used a histone proteomics approach and patient-derived neurons to show increase in histone variant H2A.Z acetylation associated with schizophrenia (SCZ). They identified the bromo- and extraterminal (BET) protein BRD4 as an H2A.

Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms.

Women are at twice the risk for anxiety and depression disorders as men are, although the underlying biological factors and mechanisms are largely unknown. In this review, we address this sex disparity at both the etiological and mechanistic level. We dissect the role of fluctuating sex hormones as a critical biological factor contributing to the increased depression and anxiety risk in women.

Sex-specific multi-level 3D genome dynamics in the mouse brain.

The female mammalian brain exhibits sex hormone-driven plasticity during the reproductive period. Recent evidence implicates chromatin dynamics in gene regulation underlying this plasticity. However, whether ovarian hormones impact higher-order chromatin organization in post-mitotic neurons in vivo is unknown.

Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.

Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 10-10-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography.

Cell type-specific chromatin accessibility analysis in the mouse and human brain.

The Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) is becoming popular in the neuroscience field where chromatin regulation is thought to be involved in neurodevelopment, activity-dependent gene regulation, hormonal and environmental responses, and pathophysiology of neuropsychiatric disorders. The advantages of using ATAC-seq include a small amount of material needed, fast protocol, and the ability to capture a range of gene regulatory elements with a single assay. With increasing interest in chromatin research, it is an imperative to have feasible, reliable assays that are compatible with a range of neuroscience study designs.

Chromatin organization in the female mouse brain fluctuates across the oestrous cycle.

Male and female brains differ significantly in both health and disease, and yet the female brain has been understudied. Sex-hormone fluctuations make the female brain particularly dynamic and are likely to confer female-specific risks for neuropsychiatric disorders. The molecular mechanisms underlying the dynamic nature of the female brain structure and function are unknown.

Sex and Estrous Cycle Effects on Anxiety- and Depression-Related Phenotypes in a Two-Hit Developmental Stress Model.

Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology.

Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome.

Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas.

Sex-Specific Epigenetics: Implications for Environmental Studies of Brain and Behavior.

Purpose Of Review: This review discusses the current state of knowledge on sex differences in the epigenetic regulation in the brain and highlights its relevance for the environmental studies of brain and behavior.

Recent Findings: Recent evidence shows that epigenetic mechanisms are involved in the control of brain sexual differentiation and in memory-enhancing effects of estradiol in females. In addition, several studies have implicated epigenetic dysregulation as an underlying mechanism for sex-specific neurobehavioral effects of environmental exposures.

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders.

Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor ( and brain-derived neurotrophic factor ().

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition.

Background: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored.

Methods: We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study.

Practical Guidelines for High-Resolution Epigenomic Profiling of Nucleosomal Histones in Postmortem Human Brain Tissue.

Background: The nervous system may include more than 100 residue-specific posttranslational modifications of histones forming the nucleosome core that are often regulated in cell-type-specific manner. On a genome-wide scale, some of the histone posttranslational modification landscapes show significant overlap with the genetic risk architecture for several psychiatric disorders, fueling PsychENCODE and other large-scale efforts to comprehensively map neuronal and nonneuronal epigenomes in hundreds of specimens. However, practical guidelines for efficient generation of histone chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) datasets from postmortem brains are needed.

The PsychENCODE project.

Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems.

Epigenetic Basis of Mental Illness.

Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. While genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. Environmental factors such as stress are known to play a role in the onset of these illnesses.

Interneuron epigenomes during the critical period of cortical plasticity: Implications for schizophrenia.

Schizophrenia, a major psychiatric disorder defined by delusions and hallucinations, among other symptoms, often with onset in early adulthood, is potentially associated with molecular and cellular alterations in parvalbumin-expressing fast spiking interneurons and other constituents of the cortical inhibitory GABAergic circuitry. The underlying mechanisms, including the role of disease-associated risk factors operating in adolescence such as drug abuse and social stressors, remain incompletely understood. Here, we summarize emerging findings from animal models, highlighting the ability of parvalbuminergic interneurons (PVI) to induce, during the juvenile period, long-term plastic changes in prefrontal and visual cortex, thereby altering perception, cognition and behavior in the adult.

DNA methylation of BDNF as a biomarker of early-life adversity.

Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior.