A new link between transcriptional initiation and pre-mRNA splicing: The RNA binding histone variant H2A.B

Soboleva, Tatiana; Parker, Brian J.; Nekrasov, Maxim; Hart‐Smith, Gene; Tay, Ying Jin; Tng, Wei Quan; Wilkins, Marc R.; Ryan, Daniel P.; Tremethick, David J.

doi:10.1371/journal.pgen.1006633

Cited by 42 publications

(85 citation statements)

References 52 publications

(93 reference statements)

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“…Li et al, 2005, Raisner et al, 2005, Ku et al, 2012), the distribution of H2A.Z in the hippocampus, a brain region critical for memory formation, is not well characterized (but see Soboleva et al, 2017). To determine the extent of hippocampal H2A.Z binding and identify regulatory regions bound by H2A.Z, we combined H2A.Z chromatin immunoprecipitation (ChIP) with next-generation sequencing.…”

Section: Resultsmentioning

confidence: 99%

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus

et al. 2018

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Summary Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.Z occupancy is positively associated with steady-state transcription, whereas learning-induced H2A.Z removal is associated with learning-induced gene expression. AAV-mediated H2A.Z depletion enhanced fear memory and resulted in gene-specific alterations of learning-induced transcription, reinforcing the role of H2A.Z as a memory suppressor. H2A.Z accumulated with age, although it remained sensitive to learning-induced eviction. Learning-related H2A.Z removal occurred at largely distinct genes in young vs old mice, suggesting that H2A.Z is subject to regulatory shifts in the aged brain despite similar memory performance. When combined with prior evidence of H3.3 accumulation in neurons, our data suggest that nucleosome composition in the brain is reorganized with age.

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Section: Resultsmentioning

confidence: 99%

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus

et al. 2018

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“…Indeed, perhaps the most striking functional feature of H2A.B and H2A.B.3 is that its N-terminus is an RNA binding module. This provides a direct link between chromatin structure and RNA function (see below) [14]. The unstructured N-terminal tails of all the H2A.B family members lack lysine residues but are enriched with arginine, serine and glycine residues, which is a common feature of many RNA binding proteins that contain unstructured regions responsible for their RNA binding activity ( Figure 1B) [42].…”

Section: Features Of Short Histone H2a Variant Proteins and Their Impmentioning

confidence: 99%

“…As mentioned above, one key aspect of the function of mouse short histone variants is the timing of their expression in the testis. H2A.B.3 expression begins during meiosis (the late pachytene stage) and peaks in post-meiotic round spermatids [14,22]. When round spermatids begin to elongate, H2A.B.3 is exported out of the nucleus, which is concurrent with the cessation of transcription [14].…”

Section: The Role Of H2al2 In the Exchange Of Histones With Protaminesmentioning

confidence: 99%

“…The short H2A histone variant family are the most divergent of the histone H2A variant family (<50% amino acid identity with canonical H2A; Figure 1) [5,13]. The best characterised of these variants are mice H2A.B.3 (involved in gene activation and splicing) [14] and H2A.L.2 (required for the histone-protamine exchange process) [20] (see below). H2A.B was first identified by Chadwick and Willard in an EST human database and overexpression of this variant in female somatic cells revealed that it was excluded from the inactive X chromosome (the Barr body) [21].…”

Section: Introductionmentioning

confidence: 99%

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Short Histone H2A Variants: Small in Stature but not in Function

Jiang

Soboleva

Tremethick

2020

Cells

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The dynamic packaging of DNA into chromatin regulates all aspects of genome function by altering the accessibility of DNA and by providing docking pads to proteins that copy, repair and express the genome. Different epigenetic-based mechanisms have been described that alter the way DNA is organised into chromatin, but one fundamental mechanism alters the biochemical composition of a nucleosome by substituting one or more of the core histones with their variant forms. Of the core histones, the largest number of histone variants belong to the H2A class. The most divergent class is the designated "short H2A variants" (H2A.B, H2A.L, H2A.P and H2A.Q), so termed because they lack a H2A C-terminal tail. These histone variants appeared late in evolution in eutherian mammals and are lineage-specific, being expressed in the testis (and, in the case of H2A.B, also in the brain). To date, most information about the function of these peculiar histone variants has come from studies on the H2A.B and H2A.L family in mice. In this review, we describe their unique protein characteristics, their impact on chromatin structure, and their known functions plus other possible, even non-chromatin, roles in an attempt to understand why these peculiar histone variants evolved in the first place.

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“…This group includes the canonical H2A histone as well as the H2A.B, H2A.L, H2A.P, H2A.W, H2A.Z, H2A.X, and macroH2A variants (24). Of particular note, H2A.B (which was formerly referred to as H2A.Bbd for Barr-body-deficient) is associated with DNA synthesis, splicing, and transcription upregulation (23)(24)(25)(26)(27)(28)(29). It was first described by Chadwick and Willard as a histone variant that is excluded from the inactive X chromosome of females and is localized to H4 hyperacetylated regions (30).…”

Section: Introductionmentioning

confidence: 99%

Effects of H2A.B incorporation on nucleosome structures and dynamics

Kohestani

Weresczczynski

2020

Preprint

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The H2A.B histone variant is an epigenetic regulator involved in transcriptional upregulation, DNA synthesis, and splicing that functions by replacing the canonical H2A histone in the nucleosome core particle. Introduction of H2A.B results in less compact nucleosome states with increased DNA unwinding and accessibility at the nucleosomal entry and exit sites. Despite being well characterized experimentally, the molecular mechanisms by which H2A.B incorporation alters nucleosome stability and dynamics remain poorly understood. To study the molecular mechanisms of H2A.B, we have performed a series of conventional and enhanced sampling molecular dynamics simulation of H2A.B and canonical H2A containing nucleosomes. Results of conventional simulations show that H2A.B weakens protein/protein and protein/DNA interactions at specific locations throughout the nucleosome. These weakened interactions result in significantly more DNA opening from both the entry and exit sites in enhanced sampling simulations. Furthermore, free energy profiles show that H2A.B containing nucleosomes have significantly broader free wells, and that H2A.B allows for sampling of states with increased DNA breathing, which are shown to be stable on the hundreds of nanoseconds timescale with further conventional simulations. Together, our results show the molecular mechanisms by which H2A.B creates less compacted nucleosome states as a means of increasing genetic accessibility and gene transcription.SIGNIFICANCENature has evolved a plethora of mechanisms for altering the physical and chemical properties of chromatin fibers as a means of controlling gene expression. These epigenetic processes may serve to increase or decrease DNA accessibility, manage the recruitment of remodeling factors, or tune the stability of the nucleosomes that make up chromatin. Here, we have used both conventional and enhanced sampling molecular dynamics simulations to understand how one of these epigenetic mechanisms, the substitution of canonical H2A proteins with the H2A.B variant, exerts its influence on the structures and dynamics of the nucleosome. Results show at the molecular level how this variant alters inter-molecular interactions to increase DNA accessibility as a means of increasing genetic accessibility and gene transcription.

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A new link between transcriptional initiation and pre-mRNA splicing: The RNA binding histone variant H2A.B

Cited by 42 publications

References 52 publications

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus

Short Histone H2A Variants: Small in Stature but not in Function

Effects of H2A.B incorporation on nucleosome structures and dynamics

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