Role of the histone variant H2A.Z.1 in memory, transcription, and alternative splicing is mediated by lysine modification.

Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histones are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies implicate histone variants as novel regulators of memory, effects of PTMs on the function of histone variants are rarely considered.

Histone macroH2A1 is a stronger regulator of hippocampal transcription and memory than macroH2A2 in mice.

Histone variants H2A.Z and H3.3 are epigenetic regulators of memory, but roles of other variants are not well characterized.

The histone chaperone Anp32e regulates memory formation, transcription, and dendritic morphology by regulating steady-state H2A.Z binding in neurons.

Rapid removal of histone H2A.Z from neuronal chromatin is a key step in learning-induced gene expression and memory formation, but mechanisms underlying learning-induced H2A.Z removal are unclear.

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer's disease-associated markers in 3xTg-AD mice.

Background: Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer's disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype.

Epigenetic Mechanisms of Learning and Memory: Implications for Aging.

The neuronal epigenome is highly sensitive to external events and its function is vital for producing stable behavioral outcomes, such as the formation of long-lasting memories. The importance of epigenetic regulation in memory is now well established and growing evidence points to altered epigenome function in the aging brain as a contributing factor to age-related memory decline. In this review, we first summarize the typical role of epigenetic factors in memory processing in a healthy young brain, then discuss the aspects of this system that are altered with aging.

Histone H2A.Z is required for androgen receptor-mediated effects on fear memory.

Epigenetic factors translate environmental signals into stable outcomes, but how they are influenced by regulators of plasticity remain unclear. We previously showed that androgen receptor overexpression inhibited fear memory in male mice and increased expression of the histone variant H2A.Z, a novel epigenetic regulator of memory.

Epigenetics and memory: an expanded role for chromatin dynamics.

Nearly two decades of research on epigenetic mechanisms in the brain have demonstrated that epigenetic marks that were once thought to be relatively static are dynamically and reversibly regulated in the brain during memory formation. Here, we focus on new research that has further expanded the dynamic nature of chromatin in memory formation through three key mechanisms. First, we discuss the emerging role of histone variants, which undergo learning-induced turnover or exchange, a process in which one histone type replaces another in chromatin.

Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain.

Emerging evidence suggests that histone variants are novel epigenetic regulators of memory, whereby histone H2A.Z suppresses fear memory. However, it is not clear if altered fear memory can also modify risk for PTSD, and whether these effects differ in males and females.

Deciphering the Enigma of the Histone H2A.Z-1/H2A.Z-2 Isoforms: Novel Insights and Remaining Questions.

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription.

Hormone-epigenome interactions in behavioural regulation.

Interactions between hormones and epigenetic factors are key regulators of behaviour, but the mechanisms that underlie their effects are complex. Epigenetic factors can modify sensitivity to hormones by altering hormone receptor expression, and hormones can regulate epigenetic factors by recruiting epigenetic regulators to DNA. The bidirectional nature of this relationship is becoming increasingly evident and suggests that the ability of hormones to regulate certain forms of behaviour may depend on their ability to induce changes in the epigenome.

Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice.

Memory formation is a protracted process that initially involves the hippocampus and becomes increasingly dependent on the cortex over time, but the mechanisms of this transfer are unclear. We recently showed that hippocampal depletion of the histone variant H2A.Z enhances both recent and remote memories, but the use of virally mediated depletion reduced H2A.

Androgen receptor is a negative regulator of contextual fear memory in male mice.

Although sex-hormones have a well-documented role in memory formation, most literature has focused on estrogens, whereas the role of androgens and their receptor (the androgen receptor; AR) in fear memory is relatively unexplored. To address this gap, we used a transgenic mouse model of AR overexpression (CMV-AR) to determine if AR regulates fear memory, and if this effect can be reversed either by the removal of circulating androgens via gonadectomy, or by antagonising AR activity with flutamide. We found that AR overexpression results in reduced freezing in response to foot shock, and that this difference is reversed with both gonadectomy and flutamide treatment.

Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice.

The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer's disease (AD) because it develops both amyloid-β (Aβ) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease.

Sex- and brain region-specific patterns of gene expression associated with socially-mediated puberty in a eusocial mammal.

The social environment can alter pubertal timing through neuroendocrine mechanisms that are not fully understood; it is thought that stress hormones (e.g., glucocorticoids or corticotropin-releasing hormone) influence the hypothalamic-pituitary-gonadal axis to inhibit puberty.

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus.

Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.

A rapid enhancement of locomotor sensitization to amphetamine by estradiol in female rats.

Estradiol moderates the effects of drugs of abuse in both humans and rodents. Estradiol's enhancement of behavioral effects resulting from high (>2.5mg/kg) doses of amphetamine is established in rats; there is less evidence for the role of estradiol in locomotor effects elicited by lower doses, which are less aversive, increase incentive motivation, involve different neural mechanisms than higher doses, and often more readily reveal group differences than do higher doses.

Advanced In vivo Use of CRISPR/Cas9 and Anti-sense DNA Inhibition for Gene Manipulation in the Brain.

Gene editing tools are essential for uncovering how genes mediate normal brain-behavior relationships and contribute to neurodegenerative and neuropsychiatric disorders. Recent progress in gene editing technology now allows neuroscientists unprecedented access to edit the genome efficiently. Although many important tools have been developed, here we focus on approaches that allow for rapid gene editing in the adult nervous system, particularly CRISPR/Cas9 and anti-sense nucleotide-based techniques.

Memory-Associated Dynamic Regulation of the "Stable" Core of the Chromatin Particle.

Chromatin is a critical regulator of neural plasticity, but basic principles of chromatin function in neurons are unclear. In this issue of Neuron, Maze et al. (2015) establish histone H3.

H2A.Z helps genes remember their history so we can remember ours.

Histone variant exchange is a novel epigenetic regulator of cognition. We speculate that H2A.Z, a variant of canonical histone H2A, exerts unique effects on transcription during distinct stages of memory formation, ultimately acting to maintain memory of previous transcriptional states and poise genes for re-activation.

Histone H2A.Z subunit exchange controls consolidation of recent and remote memory.

Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation. Epigenetic mechanisms regulate both types of consolidation, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.

Interindividual Variability in Stress Susceptibility: A Role for Epigenetic Mechanisms in PTSD.

Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by intrusive and persistent memories of a psychologically traumatic event that leads to significant functional and social impairment in affected individuals. The molecular bases underlying persistent outcomes of a transient traumatic event have remained elusive for many years, but recent studies in rodents have implicated epigenetic modifications of chromatin structure and DNA methylation as fundamental mechanisms for the induction and stabilization of fear memory. In addition to mediating adaptations to traumatic events that ultimately cause PTSD, epigenetic mechanisms are also involved in establishing individual differences in PTSD risk and resilience by mediating long-lasting effects of genes and early environment on adult function and behavior.

Epigenetic regulation of memory formation and maintenance.

Understanding the cellular and molecular mechanisms underlying the formation and maintenance of memories is a central goal of the neuroscience community. It is well regarded that an organism's ability to lastingly adapt its behavior in response to a transient environmental stimulus relies on the central nervous system's capability for structural and functional plasticity. This plasticity is dependent on a well-regulated program of neurotransmitter release, post-synaptic receptor activation, intracellular signaling cascades, gene transcription, and subsequent protein synthesis.

Epigenetic mechanisms in learned fear: implications for PTSD.

One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of 'nature' (genes) being separate from 'nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS.