The human canonical core histone catalogue

Abstract

Core histone proteins H2A, H2B, H3, and H4 are encoded by a large family of genes distributed across the human genome. Canonical core histones contribute the majority of proteins to bulk chromatin packaging, and are encoded in 4 clusters by 65 coding genes comprising 17 for H2A, 18 for H2B, 15 for H3, and 15 for H4, along with at least 17 total pseudogenes. The canonical core histone genes display coding variation that gives rise to 11 H2A, 15 H2B, 4 H3, and 2 H4 unique protein isoforms. Although histone proteins are highly conserved overall, these isoforms represent a surprising and seldom recognised variation with amino acid identity as low as 77 % between canonical histone proteins of the same type. The gene sequence and protein isoform diversity also exceeds commonly used subtype designations such as H2A.1 and H3.1, and exists in parallel with the well-known specialisation of variant histone proteins. RNA sequencing of histone transcripts shows evidence for differential expression of histone genes but the functional significance of this variation has not yet been investigated. To assist understanding of the implications of histone gene and protein diversity we have catalogued the entire human canonical core histone gene and protein complement. In order to organise this information in a robust, accessible, and accurate form, we applied software build automation tools to dynamically generate the canonical core histone repertoire based on current genome annotations and then to organise the information into a manuscript format. Automatically generated values are shown with a light grey background. Alongside recognition of the encoded protein diversity, this has led to multiple corrections to human histone annotations, reflecting the flux of the human genome as it is updated and enriched in reference databases. This dynamic manuscript approach is inspired by the aims of reproducible research and can be readily adapted to other gene families.

Beyond the Usual Suspects: Examining the Role of Understudied Histone Variants in Breast Cancer

“…The major clusters include HIST1 on chromosome 6, HIST2 and HIST3 on chromosome 1, and HIST4 on chromosome 12. These clusters comprise canonical histones, histone variants, and pseudogenes, where some pseudogenes can also produce functional proteins [ 55 , 56 ]. In evolutionarily distant species like Saccharomyces cerevisiae , genes of partner histones (i.e., H2A and H2B that form dimers, and H3 and H4 that form tetramers) are arranged pairwise and are coordinately expressed from the same promoter region [ 18 , 57 ].…”

“…Several recent studies, however, highlight findings that many of these histones are expressed outside of the S-phase and are independent of replication, for instance: 1. Certain histones within these clusters are expressed in non-dividing cells and are independent of SLBP [ 33 , 56 , 63 ]. As an example, recent studies show that several H2B variants within the human histone clusters are produced in non-dividing cells.…”

“…The major clusters include HIST1 on chromosome 6, HIST2 and HIST3 on chromosome 1, and HIST4 on chromosome 12. These clusters comprise canonical histones, histone variants, and pseudogenes, where some pseudogenes can also produce functional proteins [55,56].…”

Histone H2B isoformH2bc27is expressed in the developing brain of mouse embryos

“…In contrast, canonical histone genes are expressed in a replication-dependent manner. The chromosomal localization of genes encoding canonical histones is usually within four distinct histone clusters, whereas histone variants are scattered outside these clusters [10,11]. Even among histone genes located within a cluster, there are some genes that yield slightly different amino acid sequences, which are referred to as isoforms from among variants [12].…”