Methylation of Lysine 4 on Histone H3: Intricacy of Writing and Reading a Single Epigenetic Mark

Abstract

Cells employ elaborate mechanisms to introduce structural and chemical variation into chromatin. Here, we focus on one such element of variation: methylation of lysine 4 in histone H3 (H3K4). We assess a growing body of literature, including treatment of how the mark is established, the patterns of methylation, and the functional consequences of this epigenetic signature. We discuss structural aspects of the H3K4 methyl recognition by the downstream effectors and propose a distinction between sequence-specific recruitment mechanisms and stabilization on chromatin through methyl-lysine recognition. Finally, we hypothesize how the unique properties of the polyvalent chromatin fiber and associated effectors may amplify small differences in methyl-lysine recognition, simultaneously allowing for a dynamic chromatin architecture.

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

“…Aberrant expression of several PHD-finger proteins is associated with a wide range of human pathologies, including cancers and neurological diseases (Baker et al, 2008). Histone H3K4 di-and trimethyla- tion sites are enriched at actively transcribed promoter and enhancer chromatin regions (Ernst and Kellis, 2010), and regulate gene expression particularly in development (Ruthenburg et al, 2007). Our screen suggests that PHD-finger proteins may also be involved in the observed global loss of Histone H3K4 dimethylation, associated with tumor recurrence in PrCa patients (Seligson et al, 2005).…”

“…Furthermore, global changes in histone modification patterns are functionally associated with cancer development and recurrence (Fraga et al, 2005;Seligson et al, 2005Seligson et al, , 2009). These epigenetic modifications are mediated by antagonizing sets of enzymatic complexes: the 'writer' proteins, which attach chromatin modifications in a site-specific manner, and the 'eraser' proteins that remove these (Ruthenburg et al, 2007). Such modifications are interpreted by 'reader' proteins that specifically bind to the modified chromatin.…”

The PHD domain of the sea urchin RAG2 homolog, SpRAG2L, recognizes dimethylated lysine 4 in histone H3 tails

“…1B) [ 28 ]. Interestingly, recent reports provide strong support for the idea that PHD domains, including those of RAG2, are amongst the recognition modules utilized by the cell to "read" the histone code in its nucleus by selectively binding to tails of histone H3 with distinct posttranscriptional modifications [reviewed in 20,21,34 ].…”

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

“…Our data indeed suggest that the differential recruitment of H3K4 HMT complexes by NF-kB proteins will govern the ability of those target genes to be induced or not by those transcription factors. Several potential mechanisms underlying the recruitment of H3K4 HMT complexes to the target genes were discussed (Ruthenburg et al, 2007). One hypothesis is the direct recruitment of H3K4 HMT complexes to selected promoters by the DNA binding factors whereas the MLL core complex components (WDR5, RBBP5 and ASH2L) would regulate the activity but not the recruitment of those enzymatic complexes to their target loci.…”