Epigenetics in the Human Brain

Abstract

Many cellular constituents in the human brain permanently exit from the cell cycle during pre-or early postnatal development, but little is known about epigenetic regulation of neuronal and glial epigenomes during maturation and aging, including changes in mood and psychosis spectrum disorders and other cognitive or emotional disease. Here, we summarize the current knowledge base as it pertains to genome organization in the human brain, including the regulation of DNA cytosine methylation and hydroxymethylation, and a subset of (altogether 4100) residue-specific histone modifications associated with gene expression, and silencing and various other functional chromatin states. We propose that high-resolution mapping of epigenetic markings in postmortem brain tissue or neural cultures derived from induced pluripotent cells (iPS), in conjunction with transcriptome profiling and whole-genome sequencing, will increasingly be used to define the molecular pathology of specific cases diagnosed with depression, schizophrenia, autism, or other major psychiatric disease. We predict that these highly integrative explorations of genome organization and function will provide an important alternative to conventional approaches in human brain studies, which mainly are aimed at uncovering group effects by diagnosis but generally face limitations because of cohort size.

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

“…Aging and age-related diseases have been associated with site-specific changes in the genome that are mediated by epigenetic mechanisms (Ben-Avraham et al, 2012;Houston et al, 2013;Ricobaraza et al, 2009). For example, studies have found that patterns of DNA methylation and histone modification change with age (Das and Tyler, 2012;Numata et al, 2012).…”

Epigenetics and depression: return of the repressed

“…Caution should also be used in extrapolating findings from pre-clinical settings to patient populations. The technical analyses of epigenetic alterations are still under development and in some instances there has been failure to replicate findings in the field of neuropsychiatric epigenetics (Houston et al, 2013). For example, inconsistent results have been reported regarding hypermethylation of the REELIN gene promoter in brains of patients with schizophrenia (Abdolmaleky et Tochigi et al, 2008).…”

“…Variations in glia to neuron ratio can introduce a high degree of heterogeneity and thus affect reproducibility of epigenetic studies examining cohort-based effects in relatively small samples (Houston et al, 2013).…”

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

“…Altered DNA methylation has been found during brain development in several neuropsychiatric diseases [37][38][39][40]. MECP2, a well-known epigenetic regulation gene, has been reported to be truncated or aberrantly methylated in Rett syndrome and autism [41,42].…”