Transposable elements resistant to epigenetic resetting in the human germline are epigenetic hotspots for development and disease

Abstract

Despite the extensive erasure of DNA methylation in the early human germline, nearly eight percent of CpGs are resistant to the epigenetic resetting in the acutely hypomethylated primordial germ cells (week 7-9 hPGCs). Whether this occurs stochastically or represents relatively conserved layer of epigenetic information is unclear. Here we show that several predominantly hominoid-specific families of transposable elements (TEs) consistently resist DNA demethylation (henceforth called hPGC-methylated TEs or 'escapees') during the epigenetic resetting of hPGCs. Some of them undergo subsequent dynamic epigenetic changes during embryonic development. Our analysis of the fetal cerebral cortex also revealed multiple classes of young hPGC-methylated TEs within putative and established enhancers. Remarkably, specific hPGC-methylated TE subfamilies were associated with a multitude of adaptive human traits, including hair color and intelligence, and diseases including schizophrenia and Alzheimer's disease. We postulate that hPGC-methylated TEs represent potentially heritable information within the germline with a role in human development and evolution.

Epigenetic Regulation during Primordial Germ Cell Development and Differentiation

“…A similar trend was seen in recently profiled pig PGCs [Zhu et al, 2021]. Thus, it has been proposed that DNA methylation states at these regions might be heritable, with implications for transgenerational inheritance of epialleles [Tang et al, 2015;Dietmann et al, 2020] (discussed below).…”

“…Notably, several genomic regions were found to retain methylation at a higher level than the genome average and are termed "escapees" [Tang et al, 2015;Dietmann et al, 2020]. Interestingly, these correspond to gene ontology terms relating to brain-expressed loci, with potential links to neurological and metabolic disorders in humans, albeit with the caveat that neuronal genes are statistically much larger in terms of genome size [Sahakyan and Balasubramanian, 2016;Lopes et al, 2021], and possibly more likely to be enriched in genomic analyses.…”

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

“…Strikingly, KZFP genes were globally downregulated at postnatal versus prenatal stages, coincident with the upregulation of their TE targets. Recent indications from an analysis of TEs resistant to loss of DNA methylation during the wave of epigenetic reprogramming in human primordial germ cells (hPGCs) showed modest anti-correlations of KZFPs and their target TE subfamilies in prenatal neurogenesis (Dietmann et al 2020). The proposal that KZFPs may mediate the exaptation of TEs as developmental enhancers marked in hPGCs is intriguing and, combined with our analyses, suggests a multifaceted KZFP and TE mediated spatiotemporal transcriptional network, not only in prenatal stages but also highly prevalent after birth, with TEeRS playing important roles as alternative promoters, in addition to enhancers, throughout.…”

Grandmaternal smoking during pregnancy is associated with differential DNA methylation in their grandchildren

“…As some DNAm sites have been shown to escape the wave of de-methylation in germ cells (4), we tested the hypothesis that these sites are associated with grandmaternal smoking during pregnancy. To do this we took the 116,618 regions of the genome that have been identified as escaping de-methylation (4) (which have recently been made available as supplementary material in a bioRxiv paper (29)). We identified all sites on the EPIC array that were within those genomic regions (n=36,051) and tested them for association with grandmaternal smoking at Bonferroni corrected significance (p<0.05/36051=1.4e-6).…”