Replication-dependent histone isoforms: a new source of complexity in chromatin structure and function

Abstract

Replication-dependent histones are expressed in a cell cycle regulated manner and supply the histones necessary to support DNA replication. In mammals, the replication-dependent histones are encoded by a family of genes that are located in several clusters. In humans, these include 16 genes for histone H2A, 22 genes for histone H2B, 14 genes for histone H3, 14 genes for histone H4 and 6 genes for histone H1. While the proteins encoded by these genes are highly similar, they are not identical. For many years, these genes were thought to encode functionally equivalent histone proteins. However, several lines of evidence have emerged that suggest that the replication-dependent histone genes can have specific functions and may constitute a novel layer of chromatin regulation. This Survey and Summary reviews the literature on replication-dependent histone isoforms and discusses potential mechanisms by which the small variations in primary sequence between the isoforms can alter chromatin function. In addition, we summarize the wealth of data implicating altered regulation of histone isoform expression in cancer.

A novel histone H4 variant H4G regulates rDNA transcription in breast cancer

“…H4 is known as one of the most evolutionarily conserved histones (32,33). Surprisingly H4G shares only 85% amino acid identity with human canonical H4 (Figure 1A) (19), lacking the last five amino acids of the C-terminal tail and harboring several different amino acids within the N-terminal tail and the α-helix 1, 2 and 3 domains of the histone fold (Figure 1A) (19). In addition, in comparison with its canonical histone counterpart, H4G has a higher hydrophobicity due to amino acid changes in the N-terminal tail and α-helix 3 of the core domain (Figure 1A and Supplementary Figure S1).…”

“…However, in this study, we describe the function of a previously uncharacterized H4 variant: H4G. The H4G protein lacks five amino acids in the C-terminal tail region of the canonical human histone H4, which is a region shown to be required for cell viability in yeast (17,18) and shares only 85% identity with H4 in the remaining 98 amino acids (19). Several residues are changed throughout the protein at the N-terminal tail region, α1, α2 and α3 regions.…”

“…Several residues are changed throughout the protein at the N-terminal tail region, α1, α2 and α3 regions. The human gene HIST1H4g ( h4g ) is located in the histone cluster 1 on chromosome 6, with many other histone genes encoded nearby and is present only in hominids (16,19). Several transcriptomic data have shown that the expression of h4g is increased in T-cell prolymphocytic leukemia, HuR silenced thyroid carcinoma BCPAP cell line and an endometrioid carcinoma TOV112 cell line (20–22).…”

Functional insights from the GC-poor genomes of two aphid parasitoids,Aphidius erviandLysiphlebus fabarum

“…All eukaryotic 362 genomes examined to date contain multiple histone genes for the same histone 363 variants found in humans (e.g. 22 genes for H2B or 16 genes for H2A in humans, Singh 364 et al 2018), and it has recently been suggested that these histone variants are not 365 functionally equivalent but rather play a role in chromatin regulation (Singh et al 2018). 366…”

Extrachromosomal Histone H2B Contributes to the Formation of the Abscission Site for Cell Division

“…[1,2]. In mammals, there are different functional copies of the histone genes, which are located in a few clusters and encode several histone variants whose specific contribution to chromatin regulation is becoming clear [3,4,5,6,7]. In addition to chromatin structure and function, extrachromosomal activities of histones are emerging.…”