Epigenetic regulation of the neural transcriptome and alcohol interference during development

Abstract

Alcohol intoxicated cells broadly alter their metabolites – among them methyl and acetic acid can alter the DNA and histone epigenetic codes. Together with the promiscuous effect of alcohol on enzyme activities (including DNA methyltransferases) and the downstream effect on microRNA and transposable elements, alcohol is well placed to affect intrinsic transcriptional programs of developing cells. Considering that the developmental consequences of early alcohol exposure so profoundly affect neural systems, it is not unfounded to reason that alcohol exploits transcriptional regulators to challenge canonical gene expression and in effect, intrinsic developmental pathways to achieve widespread damage in the developing nervous system. To fully evaluate the role of epigenetic regulation in alcohol-related developmental disease, it is important to first gather the targets of epigenetic players in neurodevelopmental models. Here, we attempt to review the cellular and genomic windows of opportunity for alcohol to act on intrinsic neurodevelopmental programs. We also discuss some established targets of fetal alcohol exposure and propose pathways for future study. Overall, this review hopes to illustrate the known epigenetic program and its alterations in normal neural stem cell development and further, aims to depict how alcohol, through neuroepigenetics, may lead to neurodevelopmental deficits observed in fetal alcohol spectrum disorders.

Global DNA Methylation and Histone Posttranslational Modifications in Human and Nonhuman Primate Brain in Association with Prenatal Alcohol Exposure

“…Similarly, in dentate granule neurons of the developing mouse hippocampus, a methylation gradient correlates with the outside‐in pattern of neuronal maturation (Chen et al., ). Studies of rat and mouse brains have demonstrated associations between development and histone PTM changes (Cho et al., ; Hahn et al., ; Podobinska et al., ; Resendiz et al., ; Zhang et al., ). In order for stem cells to change from totipotency to pluripotency, active histone PTMs are present on gene promoters such as H3K27ac and H3K4me3.…”

“…When a brain cell is fully differentiated, repressive histone PTMs such as H3K27me3 are typically dominant (Podobinska et al., ). H3K4me2 and histone acetylation levels increase during differentiation of mouse NPCs (Resendiz et al., ; Zhang et al., ). Compared to NPCs, mature mouse cortical neurons are enriched in histone acetylation marks (Cho et al., ).…”

“…However, in the SVZ no significant changes were observed. Ethanol has profound effects on the on survival and proliferation of NPCs (Boschen and Klintsova, ; Resendiz et al., ; Smith et al., ; Wilhelm and Guizzetti, ). This toxicity could account for the microcephaly in FASD (De La Monte and Kril, ; Jarmasz et al., ).…”

Disconnect between alcohol-induced alterations in chromatin structure and gene transcription in a mouse embryonic stem cell model of exposure

“…In recent years, alterations to chromatin structure induced by environmental and/or nutritional insults have become an attractive explanation for the persistence of exposure effects into subsequent life stages (Feil & Fraga, 2011). Indeed, numerous studies have demonstrated that ethanol (EtOH) has the capacity to alter chromatin structure, suggesting that epigenetic mechanisms are relevant to the dysgenesis associated with FASDs (Basavarajappa & Subbanna, 2016; Mead & Sarkar, 2014; Resendiz, Mason, Lo & Zhou, 2014; Ungerer, Knezovich & Ramsay, 2013). For example, work from a number of laboratories have demonstrated both acute and long-term EtOH exposures influence patterns of DNA methylation (Ungerer et al, 2013).…”

DNA Methylation program in normal and alcohol-induced thinning cortex

“…A key finding is that during the formation of multi-layer cytoarchitecture of the cortex, 5mC and 5hmC marks are dynamically established in the progression of neuroprogenitor cell differentiation, which is in many ways similar to our previous observation of neuroepithelial cells (NEs) in neural tube and hippocampus formation. Commonly, the escalation of 5mC in the NEs marks the preparation and initiation of specification toward neural cells, likely occurring to assist in the down-regulation of multi-potent and proliferation genes (Kim et al, 2014; Resendiz, Mason, Lo, & Zhou, 2014). 5mC subsequently declines as migration begins from the upper limits of the VZ and through the IZ and enters a second cycle of up-regulation in the upper cortical layers as maturing neurons prepare for synaptogenesis.…”