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

Abstract

Histone variants, present in various cell types and tissues, are known to exhibit different functions. For example, histone H3.3 and H2A.Z are both involved in gene expression regulation, whereas H2A.X is a specific variant that responds to DNA double-strand breaks. In this study, we characterized H4G, a novel hominidae-specific histone H4 variant. We found that H4G is expressed in a variety of human cell lines and exhibit tumor-stage dependent overexpression in tissues from breast cancer patients. We found that H4G localized primarily to the nucleoli of the cell nucleus. This localization was controlled by the interaction of the alpha-helix 3 of the histone fold motif with a histone chaperone, nucleophosmin 1. In addition, we found that modulating H4G expression affects rRNA expression levels, protein synthesis rates and cell-cycle progression. Our data suggest that H4G expression alters nucleolar chromatin in a way that enhances rDNA transcription in breast cancer tissues.

H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles

“…H2A expression is stronger during S phase 45 , however, low level of H2A expression is probably sufficient in post-mitotic cells. This is the case for histone H4 for which there is no known variant in the mouse genome (to our knowledge H4 has a variant only in hominids 4 ). If H4 is expressed at low levels from one of the histone clusters, H2A might be as well.…”

“…Histone variants are non-allelic isoforms of conventional histones 1,2 . Each histone has histone variants even H4 but only in hominids 1,3,4 . Histone variants differ in their primary sequence, transcriptional regulation and timing of expression during the cell cycle compared to conventional histones [1][2][3] .…”

Primate-specific histone variants

“…Since there are no h4r homologs in other species, it was believed that histone H4 is the only histone that does not have any functionally distinct histone variant (Holmes et al 2005). Recently, H4G (histone H4-like protein type G) was found to be a hominidae-specific histone variant that drives breast cancer proliferation through the formation of a temporary nucleoprotein complex (Long et al 2019;Pang et al 2020). Located in histone cluster 1 on chromosome 6 (6p22.1-22.2) in humans, the uninterrupted gene H4C7 (h4g), which was previously known as HIST1H4G or H4FL, encodes the H4G protein (Brown et al 2015;Singh et al 2018).…”

Chromatin regulation and dynamics in stem cells

“…Although mammalian variants of H2B exist, they are often highly cell type-specific and commonly involved in gametogenesis (Draizen et al, 2016). A variant of histone H4, H4G, has very recently been discovered (Long et al, 2019), but as little is known about it at present, this section will focus on variants of H2A and H3, as they are highly conserved general regulators with numerous well-defined roles.…”