br Competing interests br Transparency document br Authors
Acknowledgments This work was supported by the Spanish Ministry of Economy and Business through the grant Plan Estatal SAF2017-83372-R (FEDER funds/UE) and MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”.
Introduction Epigenetics, defined as regulation of gene expression by introducing functional modifications in DNA without any alteration in the genomic sequence, has emerged as an integral component of Filipin Complex inhibitor development, aging and various central nervous system (CNS) disorders [1,2]. The epigenome, consisting of epigenetic marks such as DNA methylation and histone post-translational modifications (PTMs), mediates the influence of the environment on the genome and regulates the cascade of transcriptional programs crucial for both stability and plasticity of neuronal circuits . Epigenetic plasticity at all stages of brain development and aging has important implications for the etiology and potential treatment of brain-related disorders [, , , ]. Dysregulated epigenetic machinery during critical stages of prenatal and postnatal development can reprogram key functional genes, altering the normal course of brain development, maturation and aging. The functional consequences of resulting aberrant gene function may increase the risk for psychiatric or neurodegenerative disorders [, , ]. Epigenetic modifications critical for normal brain development are also integral to organization and maintenance of sex differences in the brain . Epigenetic mechanisms are linked to expression of sex differences in virtually every aspect of brain development [, , ] and thus, it is not surprising that males and females display differences in susceptibility, onset, pathogenesis, and severity of a variety of brain disorders. Unfortunately, our understanding of etiology of brain disorders and the origin of sex differences in expression of these disorders is far from clear. One reason for this is lack of complete understanding of the normal course of brain development and maturation in female brains as until recently, the majority of the developmental brain studies have used primarily male subjects. Even in studies where both sexes were used, sex has not been independently considered as a variable influencing various outcomes. In this review, we emphasize that the foundation for sex differences in risk of developing specific brain disorders may be laid during early development and further influenced by sex-specific epigenetic, hormonal signals and external environmental influences occurring throughout life. We will discuss how sex-specific expression of epigenetic machinery genes, particularly those involved in modifying the histone proteins, and the sex-specific deposition of histone marks in the developing fetal brain and placenta may create ‘sex-specific epigenetic marks’ that may play a role in programming sex-related expression of certain brain disorders. The majority of studies have focused on defining the sex-specific epigenetic profile for DNA methylation and relatively few have investigated the role of histone PTMs in sex-specific outcomes. Since histone PTMs are primary epigenetic modifications involved in regulating chromatin accessibility and transcriptional activity in the brain, this review highlights that more dedicated efforts are needed in the future to more fully understand the contribution of histone PTMs in the establishment and manifestation of sex-specific neurodevelopmental outcomes and development of CNS diseases/disorders. More than a hundred type of modifications have been identified including variations of acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, ADP-ribosylation, proline isomerization and biotinylation, and a considerable number of combinations of these modifications are possible . The information contained in a single or combination of histone marks determines the functional state of the associated DNA, referred to as the histone code [16,17]. These various histone PTMs together determine the active and silenced (or repressive) chromatin states at both global and gene-specific levels (Fig. 1a and b). Enzymes that establish these modifications on histone tails are called writers or erasers and those recognizing these modifications are called readers which may stabilize the chromatin signature by recruiting other factors [, , ]. For example, histone acetyltransferases (HAT-a writer) acetylate the lysine residues of the histone tails, histone deacetylases (HDAC-an eraser) removes acetyl groups from histones and bromodomain (a reader) recognizes acetylated lysine residues. A specific stimulus or a combination of stimuli may result in the orchestration of histone PTMs at a particular gene, determining the transcriptional output of the associated gene.