Histone H3.3 maintains genome integrity during mammalian development

Jang, Chuan Wei; Shibata, Yoichiro; Starmer, Joshua; Yee, Della; Magnuson, Terry

doi:10.1101/gad.264150.115

Cited by 171 publications

(192 citation statements)

References 95 publications

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“…H3.3 is essential for development as it is necessary for proper trimethylation of H3K27 at genes regulated by the polycomb‐repressive complex 2 (Banaszynski et al , 2013). Complete absence of H3.3 in mice thus results in peri‐implantation lethality (Jang et al , 2015). …”

Section: Introductionmentioning

confidence: 99%

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

et al. 2016

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Immunoglobulin diversification is driven by activation‐induced deaminase (AID), which converts cytidine to uracil within the Ig variable (IgV) regions. Central to the recruitment of AID to the IgV genes are factors that regulate the generation of single‐stranded DNA (ssDNA), the enzymatic substrate of AID. Here, we report that chicken DT40 cells lacking variant histone H3.3 exhibit reduced IgV sequence diversification. We show that this results from impairment of the ability of AID to access the IgV genes due to reduced formation of ssDNA during IgV transcription. Loss of H3.3 also diminishes IgV R‐loop formation. However, reducing IgV R‐loops by RNase HI overexpression in wild‐type cells does not affect IgV diversification, showing that these structures are not necessary intermediates for AID access. Importantly, the reduction in the formation of AID‐accessible ssDNA in cells lacking H3.3 is independent of any effect on the level of transcription or the kinetics of RNAPII elongation, suggesting the presence of H3.3 in the nucleosomes of the IgV genes increases the chances of the IgV DNA becoming single‐stranded, thereby creating an effective AID substrate.

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Section: Introductionmentioning

confidence: 99%

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

et al. 2016

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“…2E). We compared our gene expression profile with that of the H3.3 null embryos in a p53-null background (Jang et al 2015) and to H3.3B-KO/H3.3A-Kd ESCs (Banaszynski et al 2013). Even though all 3 studies indicate very little impact on (Jang et al 2015) and in H3.3-depleted embryonic stem cells (Banaszynski et al 2013 global transcription, an overlap between the datasets was essentially non-existent and limited to 9 genes by comparison with the H3.3-depleted embryos, and 6 genes compared with the H3.3-depleted ESCs (Fig.…”

Section: H33 Depletion Has a Mild Effect On The Global Transcriptomementioning

confidence: 99%

“…There is an increase in mitotic defects and consequent aneuploidy as well as DNA damage in H3.3B knock-out mouse embryonic fibroblasts (MEF) (Bush et al 2013) and H3.3 depleted embryonic stem cells (ESCs) (Banaszynski et al 2013), which is indicative of chromosome structure dysfunction. Heterochromatin at telomeric, centromere, and pericentromeric repeat sequences presents a more open structure in the absence of H3.3, indicating a role for H3.3 in chromatin compaction (Jang et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…It would thus be expected that transcription levels be highly impacted in the absence of H3.3. Intriguingly, however, studies in the developing embryo have shown that H3.3 depletion appears to have limited effect on gene transcription; instead, it seems to play an important role in the maintenance of genomic integrity (Bush et al 2013;Jang et al 2015). There is an increase in mitotic defects and consequent aneuploidy as well as DNA damage in H3.3B knock-out mouse embryonic fibroblasts (MEF) (Bush et al 2013) and H3.3 depleted embryonic stem cells (ESCs) (Banaszynski et al 2013), which is indicative of chromosome structure dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Histone H3.3 regulates mitotic progression in mouse embryonic fibroblasts

Örs

Papin

Favier

et al. 2017

Biochem. Cell Biol.

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H3.3 is a histone variant that marks transcription start sites as well as telomeres and heterochromatic sites on the genome. The presence of H3.3 is thought to positively correlate with the transcriptional status of its target genes. Using a conditional genetic strategy against H3.3B, combined with short hairpin RNAs against H3.3A, we essentially depleted all H3.3 gene expression in mouse embryonic fibroblasts. Following nearly complete loss of H3.3 in the cells, our transcriptomic analyses show very little impact on global gene expression or on the localization of histone variant H2A.Z. Instead, fibroblasts displayed slower cell growth and an increase in cell death, coincident with large-scale chromosome misalignment in mitosis and large polylobed or micronuclei in interphase cells. Thus, we conclude that H3.3 may have an important under-explored additional role in chromosome segregation, nuclear structure, and the maintenance of genome integrity.Key words: H3.3, transcription, mouse embryonic fibroblasts, RNA-seq, mitosis.Résumé : H3.3 est un variant d'histone qui marque les sites d'initiation de la transcription de même que les télomères et les sites hétérochromatiques du génome. La présence de H3.3 est présumée corréler positivement avec l'état transcriptionnel de ses gènes cibles. En utilisant une stratégie génétique conditionnelle contre H3.3 combinée à un petit ARN en épingle à cheveux dirigé contre H3.3, les auteurs ont essentiellement éteint toute expression génique de H3.3 dans des fibroblastes embryonnaires de souris. À la suite de la perte quasiment complète de H3.3 dans les cellules, leurs analyses transcriptomiques montrent un très faible impact sur l'expression génique globale de même que sur la localisation du variant d'histone H2A.Z. Les fibroblastes présentent plutôt une croissance cellulaire plus lente et un accroissement de la mort cellulaire en étroite concordance avec un mauvais alignement chromosomique à grande échelle lors de la mitose et de grandes structures nucléaires polylobées et des micronoyaux dans les cellules en interphase. Ils concluent ainsi que H3.3 pourrait aussi jouer un rôle important sous-exploré dans la ségrégation des chromosomes, la structure nucléaire et le maintien de l'intégrité du génome.

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“…The presence of two copies of each of the four histone proteins generates intrinsic twofold symmetry. Variations in this basic structure can be introduced by histone variants such as CENP-A, replacing H3 in the centromeric chromatin, H2A.Z, important for transcriptional regulation, or H3.3, involved in specific developmental processes in mammalian cells (Fan et al, 2004;Falk et al, 2015;Jang et al, 2015). The histone proteins are predominantly positively charged, making them prone to associate with negatively charged surfaces, such as the nucleosomal DNA itself (Bannister & Kouzarides, 2011;Iwasaki et al, 2013).…”

Section: Chemical Probes and Nucleosome Librariesmentioning

confidence: 99%

Touch, act and go: landing and operating on nucleosomes

et al. 2016

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Chromatin-associated enzymes are responsible for the installation, removal and reading of precise post-translation modifications on DNA and histone proteins. They are specifically recruited to the target gene by associated factors, and as a result of their activity, they contribute in modulating cell identity and differentiation. Structural and biophysical approaches are broadening our knowledge on these processes, demonstrating that DNA, histone tails and histone surfaces can each function as distinct yet functionally interconnected anchoring points promoting nucleosome binding and modification. The mechanisms underlying nucleosome recognition have been described for many histone modifiers and related readers. Here, we review the recent literature on the structural organization of these nucleosome-associated proteins, the binding properties that drive nucleosome modification and the methodological advances in their analysis. The overarching conclusion is that besides acting on the same substrate (the nucleosome), each system functions through characteristic modes of action, which bring about specific biological functions in gene expression regulation.

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Histone H3.3 maintains genome integrity during mammalian development

Cited by 171 publications

References 95 publications

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

Histone H3.3 regulates mitotic progression in mouse embryonic fibroblasts

Touch, act and go: landing and operating on nucleosomes

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