Linker histone H1.5 is an underestimated factor in differentiation and carcinogenesis

Abstract

Human histone H1.5, in mice called H1b, belongs to the family of linker histones (H1), which are key players in chromatin organization. These proteins sit on top of nucleosomes, in part to stabilize them, and recruit core histone modifying enzymes. Through subtype-specific deposition patterns and numerous post-translational modifications, they fine-tune gene expression and chromatin architecture, and help to control cell fate and homeostasis. However, even though it is increasingly implicated in mammalian development, H1.5 has not received as much research attention as its relatives. Recent studies have focused on its prognostic value in cancer patients and its contribution to tumorigenesis through specific molecular mechanisms. However, many functions of H1.5 are still poorly understood. In this review, we will summarize what is currently known about H1.5 and its function in cell differentiation and carcinogenesis. We will suggest key experiments that are required to understand the molecular network, in which H1.5 is embedded. These experiments will advance our understanding of the epigenetic reprogramming occurring in developmental and carcinogenic processes.

Keywords: H1.5; cancer; development; histone isoforms; histones.

Figure 1:

Comparison of human histone 1 isoforms with a flashlight on H1.5. (A) Alignment of the 11 linker histone subtypes. Grey—similarity (the darker, the greater the extend of similarity between subtypes). Green—positively charged amino acid residues. Heavily dashed blue line, N-terminus; straight blue line, globular domain; lightly dashed blue line, C-terminus [based on Uniprot and NCBI protein-tools as well as (1)]. (B) H1.5 protein sequence. Phosphorylated residues (marked red): T10, S17, T39, T138, T155, S173, S189. Methylated residues (marked green): K27. Acetylated residues (marked blue): K17, K49, K78, 168. β-Hydroxybutyrylated residues (marked yellow): K37, K55, K67, K88, K93, K109. Succinylated residues (marked purple): K37. Citrullinated residues (marked orange): R57. Sites mutated in lymphoma patients are underlined: 73G, 84K, 89S, 101G, 123A, 214K. NTD, N-terminal domain; CGD, central globular domain; CTD, C-terminal domain. N-terminus, straight blue line; globular domain, lightly dashed blue line; C-terminus [based on Uniprot and NCBI protein-tools as well as (1, 29)]

Figure 2:

Overview over selected H1.5 functions. (A) H1.5 regulates splicing. H1.5 binding is enriched around exon borders. This is believed to slow down transcription, which decreases competition between splicing sites and hence promotes the incorporation of alternatively spliced exons into the mature mRNA. (B) Msx1 binds to the MyoD promoter and recruits H1.5, which results in chromatin condensation by an unknown mechanism and ultimately in suppression of MyoD expression. (C) Proposed mechanism of H1.5-mediated chromatin compaction. H1.5 has been shown to interact with SIRT1 and DNMT3B, which induce histone deacetylation and DNA methylation, respectively, ultimately leading to chromatin compaction. This results in the inactivation of specific genes and presumably helps silencing transposable elements