Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes

Abstract

Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction.

Poly ADP-ribosylation of SET8 leads to aberrant H4K20 methylation in mammalian nuclear genome

“…This was also demonstrated on housekeeping genes, chromatin openness, etc. (73). Furthermore, SET8 mediated H4K20me1 regulates Pol II promoter-proximal pausing by regulating H4K16ac and H4K20me3 levels and ultimately transcriptional output (74).…”

Emerging Contributions of Solid-State NMR Spectroscopy to Chromatin Structural Biology

“…H4 lysine 20 trimethylation (H4 K20me3), for example, is a hydrophobic modification thought to increase the compaction of nucleosome arrays by altering the adjacent residue side-chain interactions with DNA ( Lu et al, 2008 ). Shoaib et al used MAS NMR to show that H4 K20 mono- and tri-methylation differentially dictate tail conformation and lead to either open or closed chromatin states, respectively ( Shoaib et al, 2021 ). These conclusions were based on genomic accessibility studies, Mg 2+ precipitation experiments and 2D 1 H- 13 C INEPT correlations that focused on Val 21, a residue that is, adjacent to the modification site.…”

“…We have successfully used this strategy to prepare large amounts of nucleosome array samples that contained H3 K9me3 ( Ackermann and Debelouchina, 2019 ), the relevant modification for HP1α binding and heterochromatin formation. This strategy was also used to explore the effects of K20 methylation on the dynamics of the H4 tail ( Shoaib et al, 2021 ).…”

Single-cell profiling of transcriptome and histone modifications with EpiDamID

“…To this end, we generated clonal, inducible mESC lines for each of the following targeting domains fused to Dam: H4K20me1 mintbody, H3K27me3 mintbody, and the H3K27me3-specific CBX7 protein domain (3x tuple). While H4K20me1 is enriched over the gene body of active genes (Shoaib et al, 2021), the heterochromatic mark H3K27me3 is enriched over the promoter of developmentally regulated genes until the appropriate moment of their activation during differentiation (Boyer et al, 2006;Riising et al, 2014). As controls, we included an H3K27me3 mut mintbody construct whose antigen-binding ability is abrogated via a point mutation in the third complementarity determining region of the heavy chain (Tyr105 to Phe), and a published mESC line expressing untethered Dam (Rooijers et al, 2019).…”