Reader domain specificity and lysine demethylase-4 family function

Abstract

The KDM4 histone demethylases are conserved epigenetic regulators linked to development, spermatogenesis and tumorigenesis. However, how the KDM4 family targets specific chromatin regions is largely unknown. Here, an extensive histone peptide microarray analysis uncovers trimethyl-lysine histone-binding preferences among the closely related KDM4 double tudor domains (DTDs). KDM4A/B DTDs bind strongly to H3K23me3, a poorly understood histone modification recently shown to be enriched in meiotic chromatin of ciliates and nematodes. The 2.28 Å co-crystal structure of KDM4A-DTD in complex with H3K23me3 peptide reveals key intermolecular interactions for H3K23me3 recognition. Furthermore, analysis of the 2.56 Å KDM4B-DTD crystal structure pinpoints the underlying residues required for exclusive H3K23me3 specificity, an interaction supported by in vivo co-localization of KDM4B and H3K23me3 at heterochromatin in mammalian meiotic and newly postmeiotic spermatocytes. In vitro demethylation assays suggest H3K23me3 binding by KDM4B stimulates H3K36 demethylation. Together, these results provide a possible mechanism whereby H3K23me3-binding by KDM4B directs localized H3K36 demethylation during meiosis and spermatogenesis.

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks

“…In addition to H3R53, MG-H modifications present at H3R8 and H3R26 may have a profound impact on chromatin function. These residues are critical for the binding of the epigenetic modulators AF9 and KDM4A, respectively ( 37 , 38 ), and their adduction by MGO will alter their ability to form critical H-bonding interactions ( 37 , 38 ). Thus, the presence of MGO adducts, notably under basal conditions and across multiple cell lines, may suggest a mechanism by which cellular metabolism controls chromatin dynamics.…”

Dual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL

“…Peptide microarray assay was performed as following a previous study 55 . Specifically, the peptide array slide was blocked with blocking solution (1 × PBS, 0.05% Tween-20 pH 7.4, 1% BSA) at 4 °C overnight.…”

Caenorhabditis elegans nuclear RNAi factor SET-32 deposits the transgenerational histone modification, H3K23me3

“…H3K23 methylation was discovered in alfalfa in 1990 ( Waterborg, 1990 ) and has subsequently been found in yeast, Tetrahymena, C. elegans , mouse, rat, pig and human ( Waterborg, 1990 ; Garcia et al, 2007 ; Liu et al, 2010 ; Liu et al, 2013 ; Zhang et al, 2013 ; Papazyan et al, 2014 ; Vandamme et al, 2015 ; Sidoli et al, 2016b ; Su et al, 2016 ; Fišerová et al, 2017 ; Myers et al, 2018 ; Woodhouse et al, 2018 ; Lin et al, 2020 ). Despite its high degree of evolutionary conservation, H3K23me remains an understudied histone modification.…”