Histone Variant H3.3 Mutations in Defining the Chromatin Function in Mammals

Abstract

The systematic mutation of histone 3 (H3) genes in model organisms has proven to be a valuable tool to distinguish the functional role of histone residues. No system exists in mammalian cells to directly manipulate canonical histone H3 due to a large number of clustered and multi-loci histone genes. Over the years, oncogenic histone mutations in a subset of H3 have been identified in humans, and have advanced our understanding of the function of histone residues in health and disease. The oncogenic mutations are often found in one allele of the histone variant H3.3 genes, but they prompt severe changes in the epigenetic landscape of cells, and contribute to cancer development. Therefore, mutation approaches using H3.3 genes could be relevant to the determination of the functional role of histone residues in mammalian development without the replacement of canonical H3 genes. In this review, we describe the key findings from the H3 mutation studies in model organisms wherein the genetic replacement of canonical H3 is possible. We then turn our attention to H3.3 mutations in human cancers, and discuss H3.3 substitutions in the N-terminus, which were generated in order to explore the specific residue or associated post-translational modification.

The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes

“…Thus, these mutated histones are referred to as oncohistones [ 69 ]. The incorporation of mutant H3.3 (an oncohistone) in which the altered amino acids change PTMs could impact chromatin properties of the broad epigenetic domain and alter expression of genes with the broad epigenetic domain, contributing to diseases associated with H3.3 mutants [ 69 , 70 ].…”

Lysine 27 of histone H3.3 is a fine modulator of developmental gene expression and stands as an epigenetic checkpoint for lignin biosynthesis in Arabidopsis

“…Several studies in animals (Drosophila and mammals) have explored the effect of mutations at Lysine residues in Histone 3, providing powerful tools to interrogate their roles in vivo . Such analyses were extensively done for H3K4, K36 and K27 (Trovato et al ., 2020). In particular, the Lysine-to-Methionine substitution at K27 shows a dominant phenotype due to its prevailing inhibitory effect on PRC2 HMT (Chan et al ., 2013)(Herz et al ., 2014)(Fang et al ., 2018), thereby contributing to better understand the structural basis of H3K27me3 spreading (Justin et al ., 2016).…”

“…In particular, the Lysine-to-Methionine substitution at K27 shows a dominant phenotype due to its prevailing inhibitory effect on PRC2 HMT (Chan et al ., 2013)(Herz et al ., 2014)(Fang et al ., 2018), thereby contributing to better understand the structural basis of H3K27me3 spreading (Justin et al ., 2016). Some other studies have used more neutral substitutions with amino acids such as Alanine, revealing interesting effects on gene regulation and development (Pengelly et al ., 2013)(Leatham-Jensen et al ., 2019)(Zhang et al ., 2019)(Gehre et al ., 2020) (Trovato et al ., 2020). In contrast, a limited amount of studies reported similar approaches in plants (Iwakawa et al ., 2017)(Sanders et al ., 2017)(Lu et al ., 2018)(Yan et al ., 2020)(Lin et al ., 2018) and none of them characterized the effect of a single amino acid substitution at K27 of the ubiquitous H3 proteins, on plant growth and development.…”

Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression

“…Indeed, the functional study of individual histone PTMs presents formidable challenges, and in most organisms can only be indirect. For instance, gene-editing approaches in mammals and other metazoans are extremely demanding because canonical histones are encoded by multiple genes, making it difficult to selectively interfere with specific PTMs [ 56 ]. This paper provides a proof of concept for a new method to address these questions.…”