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  • Histone PTMs play a significant role throughout brain develo

    2019-07-05

    Histone PTMs play a significant role throughout CCK-8 price development, maturation, and aging and dysregulation of histone PTMs and genes/enzymes regulating these marks have been associated with alterations CCK-8 price in the normal course of neurodevelopment and with a plethora of neurological and psychiatric diseases/disorders (Fig. 1c) [[21], [22], [23], [24], [25], [26]]. For example, at the time of embryonic stem cell (ESCs) commitment to a neural precursor cell fate, the key developmental genes with bivalent domain containing H3K27Me3 and H3K4Me3, lose the H3K27Me3 mark and are committed to neural fate through upregulation of the demethylase Kdm6b and downregulation of the methyltransferase Ezh2 (enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit) [27,28]. Reorganization of the histone landscape consisting of the H3K4Me3 mark in prefrontal cortical neurons was shown to occur during the transition from early infancy to later childhood in humans [29]. H3K4Me-associated methyltransferases, demethylases and reader proteins have been shown to be mutated in neurodevelopmental diseases including autism and schizophrenia [30,31]. Histone acetylation, methylation and phosphorylation have been shown to modulate synaptic plasticity and memory formation [[32], [33], [34]]. Histone modifiers have been proposed as potential therapeutic targets to treat age-associated cognitive decline [35,36]. Histone PTMs, through their interaction with the genome and hormonal milieu, have emerged as important players in sexually differentiating the developing brain and regulating the expression of complex behaviors in a sex-specific manner in adulthood [11,37,38]. In the following sections, we will discuss the evidence in support of the role of histone PTMs in shaping sex differences in the brain during early and later developmental stages of life. We will also highlight their potential contribution to sex differences in manifestation of various neurological disorders with a focus on incidence, onset, and progression of psychiatric disorders of autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD).
    Sexual differentiation of brain and histone PTMs
    Psychiatric disorders: sex differences and histone PTMs
    Conclusion Despite recent interest in understanding sex differences in several physiological and behavioral processes, there remains a paucity of information related to how an individual's brain development is sculpted based on sex. Among known epigenetic mechanisms, histone PTMs and the enzymes involved in modifying histones, have emerged as important regulators of brain development, behavior, and related disorders as well as in sexually differentiating the brain. A few studies addressing the prevalence of sex differences in psychiatric disorders indicate that histone PTMs might be associated with sex-specific outcomes, but more research is needed to better understand whether they are actually causative factors leading to the sex differences in occurrence and manifestation of disease (Fig. 4). Environmental factors influence histone PTMs and hormone interactions throughout the lifespan from early development to aging and integration of these mechanisms with the brain genome in a sex-specific manner may influence the vulnerability and resiliency to psychiatric disorders. Understanding how these mechanisms interact and contribute to disease etiology has the potential to inform about development of novel interventions. Clearly, sex matters in brain development and in expression of brain disorders. The challenges for future research, however, are many due to poor understanding of (1) similarities and differences between male and brain female brains at functional, anatomical, and molecular levels; (2) molecular and functional correlates that may vary by brain region and cell type within each sex; (3) how individual experiences and responses to different types of environmental exposures across the lifespan shape the epigenome and hence the genome in a context-dependent manner; (4) the functional consequences of subtle differences at molecular level between sexes and (5) lack of proper statistical methods/design to validate the significance of such biological effects. As we move forward, it will be important to start addressing these issues.