Analysis of epigenetic mechanisms involved in brain development, degeneration and senescence using the next-generation sequencing (NGS)

Abstract

Genomic DNA is organized into chromatin, which adopts characteristic configurations when DNA interacts with transcription factors (TFs), RNA polymerase, or other regulators. Charting these configurations with genome-wide maps of histone modifications (''chromatin state maps'') represents an effective means for identifying functional DNA elements and assessing their activities in a given cell population. Signature patterns of ''active'' chromatin marks poised or active promoters, transcribed regions, and candidate enhancers. Recent studies have applied chromatin profiling to characterize enhancer dynamics and epigenetic regulatory mechanisms in differentiation, cellular reprogramming, and disease processes. In the brain, histone acetylation can be triggered by several forms of neuronal activity, as LTP induction was paralleled by increased H3 and H4 acetylation, specifically at the promoter regions of genes involved in synaptic transmission. Notably, changes in histone acetylation accompany memory consolidation; and different learning paradigms are likely to elicit distinct epigenetic signatures in the brain. The regions involved in memory formation, such as the amygdala, hippocampus and cortex express more highly the zinc-dependent histone deacetylases (HDAC1-11), and among them HDAC2 plays a pivotal part in constraining cognitive functions upon neurodegeneration, ageing and, possibly, following prolonged periods of stress.The analyses of differences in the chromatin landscape have allowed to determining the networks underlying evolutionary differences between species, developmentally expressed genes, and have significantly contributed to the genetic etiology of human diseases. This type of approach may also help understanding how environmental conditions further shape the phenotypes and affect disease risks with broad implications for human health. (AU)