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Histone post-translational modifications (PTMs) have emerged as exciting mechanisms of biological regulation, impacting pathways related to cancer, immunity, brain function, and more. Over the past decade alone, several histone PTMs have been discovered, including acylation, lipidation, monoaminylation, and glycation, many of which appear to have crucial roles in nucleosome stability and transcriptional regulation. In this review, we discuss novel histone PTMs identified within the past 10 years, with an extended focus on enzymatic versus nonenzymatic mechanisms underlying modification and adduction. Furthermore, we consider how these novel histone PTMs might fit within the framework of a so-called ‘histone code’, emphasizing the physiological relevance of these PTMs in metabolism, development, and disease states.

Neurodevelopmental disorders ranging from autism to intellectual disability display sex-biased prevalence and phenotypical presentations. Despite increasing knowledge about temporospatial cortical map development and genetic variants linked to neurodevelopmental disorders, when and how sex-biased neural circuit derailment may arise in diseased brain remain unknown. Here, we identify in mice that serotonin uptake transporter (SERT) in non-serotonergic neurons – hippocampal and prefrontal pyramidal neurons – confers sex-biased effects specifically during neural circuit development. A set of gradient-patterned CA3 pyramidal neurons transiently express SERT to clear extracellular serotonin, coinciding with hippocampal synaptic circuit establishment. Ablating pyramidal neuron SERT (SERTPyramidΔ) alters dendritic spine developmental trajectory in the hippocampus, and precipitates sex-biased impairments in long-term activity-dependent hippocampal synaptic plasticity and cognitive behaviors. Transcriptomic analyses identify sex-biased alterations in gene sets associated with autism, dendritic spine structure, synaptic function and male-specific enrichment of dysregulated genes in glial cells in early postnatal SERTPyramidΔ hippocampus. Our data suggest that SERT function in these pyramidal neurons underscores a temporal- and brain region-specific regulation of normal sex-dimorphic circuit development and a source for sex-biased vulnerability to cognitive and behavioral impairments. This article has an associated ‘The people behind the papers’ interview.

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.

Epidemiological studies from the last century have drawn strong associations between paternal life experiences and offspring health and disease outcomes. Recent studies have demonstrated sperm small non-coding RNA (sncRNA) populations vary in response to diverse paternal insults. However, for studies in retrospective or prospective human cohorts to identify changes in paternal germ cell epigenetics in association with offspring disease risk, a framework must first be built with insight into the expected biological variation inherent in human populations. In other words, how will we know what to look for if we don’t first know what is stable and what is dynamic, and what is consistent within and between men over time? From sperm samples from a ‘normative’ cohort of healthy human subjects collected repeatedly from each subject over 6 months, 17 healthy male participants met inclusion criteria and completed donations and psychological evaluations of perceived stress monthly. sncRNAs (including miRNA, piRNA, and tRNA) isolated from mature sperm from these samples were subjected to Illumina small RNA sequencing, aligned to subtype-specific reference transcriptomes, and quantified. The repeated measures design allowed us to define both within- and between-subject variation in the expression of 254 miRNA, 194 tRNA, and 937 piRNA in sperm over time. We developed screening criteria to identify a subset of potential environmentally responsive ‘dynamic’ sperm sncRNA. Implementing complex modeling of the relationships between individual dynamic sncRNA and perceived stress states in these data, we identified 5 miRNA (including let-7f-5p and miR-181a-5p) and 4 tRNA that are responsive to the dynamics of prior stress experience and fit our established mouse model. In the current study, we aligned repeated sampling of human sperm sncRNA expression data with concurrent measures of perceived stress as a novel framework that can now be applied across a range of studies focused on diverse environmental factors able to influence germ cell programming and potentially impact offspring development.

Introduction Despite a wealth of epidemiological evidence that cumulative parental lifetime stress experiences prior to conception are determinant of offspring developmental trajectories, there is a lack of insight on how these previous stress experiences are stored and communicated intergenerationally. Preconception experiences may impact offspring development through alterations in transcriptional regulation of the placenta, a major determinant of offspring growth and sex-specific developmental outcomes. We evaluated the lasting influence of maternal and paternal preconception stress (PCS) on the mid-gestation placenta and fetal brain, utilizing their transcriptomes as proximate readouts of intergenerational impact. Methods To assess the combined vs. dominant influence of maternal and paternal preconception environment on sex-specific fetal development, we compared transcriptional outcomes using a breeding scheme of one stressed parent, both stressed parents, or no stressed parents as controls. Results Interestingly, offspring sex affected the directionality of transcriptional changes in response to PCS, where male tissues showed a predominant downregulation, and female tissues showed an upregulation. There was also an intriguing effect of parental sex on placental programming where paternal PCS drove more effects in female placentas, while maternal PCS produced more transcriptional changes in male placentas. However, in the fetal brain, maternal PCS produced overall more changes in gene expression than paternal PCS, supporting the idea that the intrauterine environment may have a larger overall influence on the developing brain than it does on shaping the placenta. Discussion Preconception experiences drive changes in the placental and the fetal brain transcriptome at a critical developmental timepoint. While not determinant, these altered transcriptional states may underlie sex-biased risk or resilience to stressful experiences later in life.

Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process.We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification.The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress-induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter.Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.

Schizophrenia (SZ) is a psychiatric disorder with complex genetic risk dictated by interactions between hundreds of risk variants. Epigenetic factors, such as histone posttranslational modifications (PTMs), have been shown to play critical roles in many neurodevelopmental processes, and when perturbed may also contribute to the precipitation of disease. Here, we apply an unbiased proteomics approach to evaluate combinatorial histone PTMs in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons from individuals with SZ. We observe hyperacetylation of H2A.Z and H4 in neurons derived from SZ cases, results that were confirmed in postmortem human brain. We demonstrate that the bromodomain and extraterminal (BET) protein, BRD4, is a bona fide ‘reader’ of H2A.Z acetylation, and further provide evidence that BET family protein inhibition ameliorates transcriptional abnormalities in patient-derived neurons. Thus, treatments aimed at alleviating BET protein interactions with hyperacetylated histones may aid in the prevention or treatment of SZ.

Strained in Planning Your Mouse Background? Using the HPA Stress Axis as a Biological Readout for Backcrossing Strategies

Epidemiological studies provide strong evidence for the impact of diverse paternal life experiences on offspring neurodevelomental disease risk. While these associations are well established, the molecular mechanisms underlying these intergenerational transmissions remain elusive, though recent studies focusing on the influence of paternal experience prior to conception have implicated germ cell epigenetic programming. Any model accounting for the germline transfer of non-genetic information from sire to offspring must include certain components: 1) a vector to carry any signal from the paternal compartment to the maternal reproductive tract and future embryo; 2) a molecular signal, encoded by a paternal experience, to carry this “memory” and enact downstream responses; and 3) a target cell or tissue to receive the signal and convert it into an effect on embryonic development. In this review, we explore the field’s current understanding of the potential processes and candidate factors that may serve as these components. We specifically discuss the field’s growing appreciation for the importance of extracellular vesicles in these processes, beginning with their known role in delivering potential signals, including small RNAs, to sperm, the prototypical vector, during their post-testicular maturation. Finally we explore the possibility that paternal extracellular vesicles could themselves serve as vectors, delivering signals not only to gametes or the zygote, but also to tissues of the maternal reproductive tract to influence fetal development.

Paternal preconception exposures and insults, including stress, dietary challenge and drugs of abuse, can shape offspring health and disease risk outcomes, as evidenced from retrospective human studies and more recent animal models1–16. Mechanistic examination has implicated small noncoding RNA populations in sperm, including microRNA (miRs), as carriers of paternal environmental information that consequently influence offspring development15,17–21. However, the cellular mechanisms by which these paternal signals are relayed to sperm and how they may persist remain unknown. Here, using our previously established paternal stress mouse model we identify caput epididymal epithelial glucocorticoid receptors as crucial upstream mediators of long-lasting germ cell programming. We show that glucocorticoid treatment of caput epididymal epithelial cells results in increased glucocorticoid receptor levels and enduring changes to the miR content of secreted extracellular vesicles (EVs), or epididymosomes, known to interact with sperm and alter their RNA content22,23. Further, significant changes were detected in the caput epididymal histone code long after stress ended, both in vitro and in vivo, as a potential mechanism whereby stress programmed enduring changes to EV miRs. Genetic targeting to reduce caput epididymal epithelial-specific glucocorticoid receptors reversed stress-induced chromatin remodeling and promoted cellular resilience to paternal stress, ultimately rescuing transmission of a stress dysregulated offspring phenotype. Taken together, these studies identify glucocorticoid receptor regulation of EV miRs in the caput epididymis as a key contributor in the intergenerational transmission of paternal environmental stress experiences.

Extracellular vesicles (EVs) are a unique mode of intercellular communication capable of incredible specificity in transmitting signals involved in cellular function, including germ cell maturation. Spermatogenesis occurs in the testes, behind a protective barrier to ensure safeguarding of germline DNA from environmental insults. Following DNA compaction, further sperm maturation occurs in the epididymis. Here, we report reproductive tract EVs transmit information regarding stress in the paternal environment to sperm, potentially altering fetal development. Using intracytoplasmic sperm injection, we found that sperm incubated with EVs collected from stress-treated epididymal epithelial cells produced offspring with altered neurodevelopment and adult stress reactivity. Proteomic and transcriptomic assessment of these EVs showed dramatic changes in protein and miRNA content long after stress treatment had ended, supporting a lasting programmatic change in response to chronic stress. Thus, EVs as a normal process in sperm maturation, can also perform roles in intergenerational transmission of paternal environmental experience.

Parental stress exposures are implicated in the risk for offspring neurodevelopmental and neuropsychiatric disorders, prompting critical examination of preconception and prenatal periods as vulnerable to environmental insults such as stress. Evidence from human studies and animal models demonstrates the influence that both maternal and paternal stress exposures have in changing the course of offspring brain development. Mechanistic examination of modes of intergenerational transmission of exposure during pregnancy has pointed to alterations in placental signaling, including changes in inflammatory, nutrient-sensing, and epigenetic pathways. Transmission of preconception paternal stress exposure is associated with changes in epigenetic marks in sperm, with a primary focus on the reprogramming of DNA methylation, histone post-translational modifications, and small non-coding RNAs. In this review, we discuss evidence supporting the important contribution of intergenerational parental stress in offspring neurodevelopment and disease risk, and the currently known epigenetic mechanisms underlying this transmission.

Stress during specific developmental stages can alter the trajectory of normal neurodevelopmental processes, often leading to dysfunctional stress responsiveness, cognitive and metabolic disruptions later in life. Here we summarize our current knowledge of the effects of stress exposure during key periods of early brain development and the potential mechanisms by which stress imparts long-term changes in the developing brain. We describe the potential for lifetime stress exposures to alter the parental germ line and ultimately alter offspring brain programming. We discuss the mechanisms by which prenatal and early postnatal stress program the brain, highlighting the importance of the placenta in transmitting maternal stress signals to the developing fetus. Finally, we highlight the emerging role of the stress-sensitive gut microbiome in programming the gut-brain axis to ultimately influence brain function and behavior.

Background Diabetes, obesity, and overweight are prevalent pregnancy complications that predispose offspring to neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder, and schizophrenia. Although male individuals are three to four times more likely than female individuals to develop these disorders, the mechanisms driving the sex specificity of disease vulnerability remain unclear. Because defective placental insulin receptor (InsR) signaling is a hallmark of pregnancy metabolic dysfunction, we hypothesized that it may be an important contributor and novel mechanistic link to sex-specific neurodevelopmental changes underlying disease risk. Methods We used Cre/loxP transgenic mice to conditionally target InsRs in fetally derived placental trophoblasts. Adult offspring were evaluated for effects of placental trophoblast-specific InsR deficiency on stress sensitivity, cognitive function, sensorimotor gating, and prefrontal cortical transcriptional reprogramming. To evaluate molecular mechanisms driving sex-specific outcomes, we assessed genome-wide expression profiles in the placenta and fetal brain. Results Male, but not female, mice with placental trophoblast-specific InsR deficiency showed a significantly increased hypothalamic-pituitary-adrenal axis stress response and impaired sensorimotor gating, phenotypic effects that were associated with dysregulated nucleotide metabolic processes in the male prefrontal cortex. Within the placenta, InsR deficiency elicited changes in gene expression, predominantly in male mice, reflecting potential shifts in vasculature, amino acid transport, serotonin homeostasis, and mitochondrial function. These placental disruptions were associated with altered gene expression profiles in the male fetal brain and suggested delayed cortical development. Conclusions Together, these data demonstrate the novel role of placental InsRs in sex-specific neurodevelopment and reveal a potential mechanism for neurodevelopmental disorder risk in pregnancies complicated by maternal metabolic disorders, including diabetes and obesity.