Is H3K4me3 instructive for transcription activation?

Abstract

Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a near-universal chromatin modification at the transcription start site of active genes in eukaryotes from yeast to man and its levels reflect the amount of transcription. Because of this association, H3K4me3 is often described as an 'activating' histone modification and assumed to have an instructive role in the transcription of genes, but the field is lacking a conserved mechanism to support this view. The overwhelming finding from genome-wide studies is that actually very little transcription changes upon removal of most H3K4me3 under steady-state or dynamically changing conditions, including at mammalian CpG island promoters. Instead, rather than a major role in instructing transcription, time-resolved experiments provide more evidence supporting the deposition of H3K4me3 into chromatin as a result of transcription, influencing processes such as memory of previous states, transcriptional consistency between cells in a population and transcription termination.

A Metabolic Function for Phospholipid and Histone Methylation

“…Our series of epistatic analyses suggest a general hierarchy: PE > H3K36 > H3K79 > H3K4 in terms of cellular preference for methyl sinks. Consistent with this idea, the precise roles of H3K36 and H3K79, and even H3K4 methylation in transcriptional regulation remain uncertain, leading to numerous other proposed functions for methylation at these sites (Howe et al, 2017; Nguyen and Zhang, 2011; Wagner and Carpenter, 2012)…”

Native elongating transcript sequencing reveals global anti-correlation between sense and antisense nascent transcription in fission yeast

“…Trimethylation of histone H3 lysine 4 (H3K4me3) in the 5 ′ region of genes and of histone H3 lysine 36 (H3K36me3) across the gene body are two other hallmarks of active transcription (Smolle and Workman 2013;Howe et al 2017). In budding yeast, genes with antisense transcription display reduced H3K4me3 and H3K36me3 levels (Murray et al 2015).…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…These partners include various chromatin-regulatory complexes (Box 3) that coordinate multiple repressive histone modifications (Figure 1A). Though H3K4me3 has been historically associated with transcriptional activation, continued rise in H3K4me3 after RNA transcription peaks [26] makes it unclear whether the mark is entirely instructive for transcription or also an effect of it [27]. Furthermore, loss of H3K4me3 does not affect transcription of many genes [28], suggesting that the transcriptional repressive function of the JARID1 family is targeted to only a subset of genes and not a uniform role across the genome.…”