Global Epigenomic Reconfiguration During Mammalian Brain Development

Abstract

DNA methylation is implicated in mammalian brain development and plasticity underlying learning and memory. We report the genome-wide composition, patterning, cell specificity, and dynamics of DNA methylation at single-base resolution in human and mouse frontal cortex throughout their lifespan. Widespread methylome reconfiguration occurs during fetal to young adult development, coincident with synaptogenesis. During this period, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. Moreover, we found an mCH signature that identifies genes escaping X-chromosome inactivation. Last, whole-genome single-base resolution 5-hydroxymethylcytosine (hmC) maps revealed that hmC marks fetal brain cell genomes at putative regulatory regions that are CG-demethylated and activated in the adult brain and that CG demethylation at these hmC-poised loci depends on Tet2 activity.

DNA methylation and healthy human aging

“…Studies that examined this period of human development have reported that DNA methylation levels increase rapidly and then stabilize by adulthood in both brain and blood (Alisch et al ., 2012; Lister et al ., 2013). From adulthood to advanced age, overall levels of DNA methylation remain stable in blood, while interindividual variability increases over that time (Talens et al ., 2012; Weidner et al ., 2014).…”

“…Overall, most tissues fit with the pattern of increase in average DNA methylation early in life, with a gradual decrease later in life (Grönniger et al ., 2010; Ong & Holbrook, 2014). For example, many studies have shown that brain regions follow this pattern, showing rapid changes in DNA methylation in the early life period and then slowing gradually over the lifespan (Horvath et al ., 2012; Numata et al ., 2012 Lister et al ., 2013). Given that DNA methylation profiles are highly divergent in different tissues, comparing DNA methylation across tissues presents unique challenges.…”

“…This indicates that some people's epigenome is more concordant with their chronological age than others. When tracked in a large population, the distribution of DNA methylation levels suggests that these sites change rapidly with age until adulthood, at which point the rate of change slows considerably (Horvath, 2013; Lister et al ., 2013). An important characteristic of the epigenetic clock is that it can be tissue specific, meaning that different sites may be better correlated with age in specific tissues, although pan‐tissue epigenetic clocks have also been identified (Teschendorff et al ., 2010; Horvath et al ., 2012; Day et al ., 2013).…”

“…It is important to note that many of the studies discussed in this review have not been adjusted for differences in cellular composition with age. Therefore, tissue‐specific epigenetic clock sites in some of these studies may not be accurate; however, the overall patterns of DNA methylation change with age have been validated in studies that did correct for cellular composition (Lam et al ., 2012; Lister et al ., 2013; Jaffe & Irizarry, 2014). …”

Addiction et régulations épigénétiques

“…Chez les mammifères, cette méthylation a lieu majoritairement sur la séquence CpG, même si d'autres dinucléotides, appelés CpH (H = A/C/T), sont également susceptibles d'être méthylés. Une étude globale indique même que la méthylation mCpH serait prépondérante dans les neurones matures du cortex frontal [12]. La 5-méthylcytosine (5mC) constitue à peu près 1 % des bases totales du génome humain [13].…”