Transposable elements are regulated by context-specific patterns of chromatin marks in mouse embryonic stem cells

Abstract

The majority of mammalian genomes are devoted to transposable elements (TEs). Whilst TEs are increasingly recognized for their important biological functions, they are a potential danger to genomic stability and are carefully regulated by the epigenetic system. However, the full complexity of this regulatory system is not understood. Here, using mouse embryonic stem cells, we show that TEs are suppressed by heterochromatic marks like H3K9me3, and are also labelled by all major types of chromatin modification in complex patterns, including bivalent activatory and repressive marks. We identified 29 epigenetic modifiers that significantly deregulated at least one type of TE. The loss of Setdb1, Ncor2, Rnf2, Kat5, Prmt5, Uhrf1, and Rrp8 caused widespread changes in TE expression and chromatin accessibility. These effects were context-specific, with different chromatin modifiers regulating the expression and chromatin accessibility of specific subsets of TEs. Our work reveals the complex patterns of epigenetic regulation of TEs.

An embryonic stem cell-specific heterochromatin state allows core histone exchange in the absence of DNA accessibility

“…Remarkably, regions of highest turnover were also highly enriched for H3K9me3, concomitant with HP1 binding (Figure 2f-g). Prior analysis suggested that, as stereotypical for heterochromatin, DNA accessibility at ERVs is generally low 29 , and analysis of recent ATAC-Seq data in mESC 20 confirmed that IAPLTRs neither show defined nucleosome-free regions nor broader domains of accessible DNA (Figure 2h). In summary, we find that histone turnover does not require or induce an increase in DNA accessibility at IAP ERVs (Figure 2f), Instead, it appears that histone H3.3-H4 is swapped into chromatin directly replacing an existing H3-H4 histone dimer or tetramer, hinting at the possibility of a concerted mechanism.…”

“…Interstitial heterochromatin is highly CpG-methylated, enriched in linker histone and bound by HP1 family proteins, the stereotypical H3K9me3 readers [28][29][30] . HP1 proteins have been shown to bridge nucleosomes and compact chromatin into phase-separated liquid condensates 31,32 .…”

A Degenerate Peptide Library Approach to Reveal Sequence Determinants of Methyllysine-Driven Protein Interactions

“…Undoubtedly, ab8895 recognizes H3K4me1, but we cannot explain this solely by highaffinity interactions, as we predict 364 sequences to bind equally or better than H3K4. Likely, the community does not robustly detect off target proteins in techniques like western blot (He et al, 2019) or ChIP (Mohaghegh et al, 2019) because histones are so much more abundant, as reported by Wisniewski et al (2014). ab8895 anti-H3K4me1 LoB scores ranged from 0 to 801.5.…”

Virus-induced transposable element expression up-regulation in human and mouse host cells

“…The mobile ability of TEs make them a source of genomic instability, and thus, during normal cellular activities, they are mostly repressed by numerous epigenetic chromatin modifications (He et al, 2019). However, baseline levels of TE expression exist across different cell types (Tokuyama et al, 2018), and various sources of cellular stress can cause their up-regulation or down-regulation, which may be transient or persistent, and it is unclear how these expression changes affect the cell (Horváth et al, 2017).…”