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 >100) 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.

Figure 1

The Epigenome, from nucleus to nucleosome. Schematic illustration of (green) gene poised for transcription by polymerase II (Pol II) initiation complex, with nucleosome free interval at transcription start site (TSS). (Blue) distal enhancer sequence which in loop-like structure moves in close proximity to active gene. (Red) marks a small subset of heterochromatic portions of the genome, including silenced gene and heterochromatic structures bordering the nuclear envelope and pore complex, and also the nucleolar periphery. A small subset of representative histone variants and histone H3 site-specific lysine (K) residues at N-terminal tail (K4, K9, K27, and K36) or core fold domain of the (histone) octamer (K79) and the H4K20 residue are shown as indicated, together with panel of mono- and trimethyl, or acetyl modifications that differentiate between active promoters, transcribed gene bodies, and repressive chromatin, as indicated. DNA cytosines that are hydroxymethylated at the C5 position are mostly found at active promoters, whereas methylated cytosines are positioned within body of actively transcribed genes and around repressed promoters and in constitutive heterochromatin.

Figure 2

Flow diagram of nuclei sorting procedure, including fluorescence-activated separation and sorting of NeuN+ and NeuN− nuclei from brain tissue. For analyses of histone modifications, sorted nuclei are subjected to micrococcal nuclease-based enzymatic digestion of chromatin into mononucleosomes (∼146 bp long) for subsequent immunoprecipitation with modification-specific histone antibody.

Figure 3

Flow chart aimed at defining subject-specific genetic and epigenetic risk architectures of psychiatric disease. See text for additional details.