The Histone Variant H3.3 in Transcriptional Regulation and Human Disease

Abstract

Histone proteins wrap around DNA to form nucleosomes, which further compact into higher order structure of chromatin. In addition to the canonical histones, there are also variant histones that often have pivotal roles in regulating chromatin dynamics and the accessibility of the underlying DNA. H3.3 is the most common non-centromeric variant of histone H3 that differs from the canonical H3 by just 4–5 amino acids. Here we discuss the current knowledge of H3.3 in transcriptional regulation and the recent discoveries and molecular mechanisms of H3.3 mutations in human cancer.

Phosphorylation of the ancestral histone variant H3.3 amplifies stimulation-induced transcription

“…The macrophage response to pathogen sensing, for example, rapidly engages highly conserved signaling pathways and transcription factors (TFs) for coordination of inflammatory gene induction 1–3 . Enriched integration of histone H3.3, the ancestral histone H3 variant, is a feature of inflammatory genes and, in general, dynamically regulated chromatin and transcription 4–7 . However, little is known of how chromatin is regulated at rapidly induced genes and what features of H3.3, conserved from yeast to human, might enable rapid and high-level transcription.…”

“…S1A). Despite the well-characterized enrichment of H3.3 in dynamic chromatin, the potential regulatory roles of H3.3S31 and H3.3-specific phosphorylation are unknown 4–7,17 . Here, we report that H3.3 phosphorylation at the conserved and H3.3-specific serine 31 (H3.3S31ph) amplifies the rapid, high-level transcription of stimulation-induced gene expression.…”

Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements

“…Polyadenylation of H3.1 mRNA induced by arsenic exposure compromises assembly of H3.3 at important genomic loci. Numerous findings linked abnormal H3.3 to cancer initiation and development (Buschbeck and Hake, 2017;Jang et al, 2015;Shi et al, 2017;Soria et al, 2012;Szenker et al, 2011;Talbert and Henikoff, 2010). Moreover, H3.3-knockout mice were embryonically lethal and displayed severe chromosomal aberrations (Bush et al, 2013;Jang et al, 2015), suggesting that disruption of H3.3 assembly might be a significant contributor to arsenic-induced carcinogenesis.…”

MRX93 syndrome (BRWD3 gene): five new patients with novel mutations

“…“Mental Retardation X‐linked 93 syndrome” (MRX93; MIM# 300659) is an XLID disorder caused by pathogenic variants in BRWD3 , mapping to Xq21.1, which encodes for Bromodomain and WD‐repeat domain‐containing protein 3 (BRWD3 ) . The pathogenic mechanism associated with BRWD3 is not well understood yet, although there is an evidence that this protein is involved in the epigenetic regulation of the nervous system development and viability through the HIRA/histone H3.3 pathway . Histones are a family of proteins involved in wrapping DNA around them to form nucleosomes.…”

“…The pathogenic mechanism associated with BRWD3 is not well understood yet, although there is an evidence that this protein is involved in the epigenetic regulation of the nervous system development and viability through the HIRA/histone H3.3 pathway. 5,6 Histones are a family of proteins involved Drosophila, which plays a major role mediating the light-dependent binding of CRY (Cryptochrome). 9 In humans, pathogenic variants in several ubiquitin ligases E3-type proteins have been related with growth disorders, such as Mental retardation, X-linked, syndromic, Cabezas type (MRXSC) (gene: CUL4B) or Tenorio syndrome due to mutations in RNF125.…”