Dynamic Histone Variant Exchange Accompanies Gene Induction in T Cells

Abstract

Changes in chromatin composition are often a prerequisite for gene induction. Nonallelic histone variants have recently emerged as key players in transcriptional control and chromatin modulation. While the changes in chromatin accessibility and histone posttranslational modification (PTM) distribution that accompany gene induction are well documented, the dynamics of histone variant exchange that parallel these events are still poorly defined. In this study, we have examined the changes in histone variant distribution that accompany activation of the inducible CD69 and heparanase genes in T cells. We demonstrate that the chromatin accessibility increases that accompany the induction of both of these genes are not associated with nucleosome loss but instead are paralleled by changes in histone variant distribution. Specifically, induction of these genes was paralleled by depletion of the H2A.Z histone variant and concomitant deposition of H3.3. Furthermore, H3.3 deposition was accompanied by changes in PTM patterns consistent with H3.3 enriching or depleting different PTMs upon incorporation into chromatin. Nevertheless, we present evidence that these H3.3-borne PTMs can be negated by recruited enzymatic activities. From these observations, we propose that H3.3 deposition may both facilitate chromatin accessibility increases by destabilizing nucleosomes and compete with recruited histone modifiers to alter PTM patterns upon gene induction.

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

“…Perhaps reminiscent of that model, induction of the CD69 and heparanase genes in T cells was correlated with the depletion of H2A.Z and concomitant deposition of H3.3 on the promoter. 46 Based on these results regarding promoters, it is tempting to speculate that H2A.Z eviction during transcription elongation may also be coupled to H3.3 deposition. Experiments in Drosophila revealed that nucleosomes were lost and replaced with H3.3-containing nucleosomes during activated transcription.…”

Epigenetics in the Human Brain

“…It is generally thought that RNA polymerase and the transcriptional activation and elongation complexes destabilize nucleosomes, promoting nucleosome remodeling, and variant histone incorporation, which then further potentiate or stabilize gene expression (Bintu et al, 2011;Sutcliffe et al, 2009).…”

Myogenic transcriptional activation of MyoD mediated by replication-independent histone deposition

“…Indeed, transcription induction coincides with H3.3 accumulation at several individual genes (20)(21)(22). However, recent reports based on detailed analysis of transcriptional and developmental phenotypes of flies that have been genetically manipulated to deplete H3.3 have challenged its functional significance in active transcription (23,24), because H3.3 was dispensable for most transcriptional events throughout Drosophila development.…”