The Histone Variant H3.3 Marks Active Chromatin by Replication-Independent Nucleosome Assembly

Ahmad, Kami; Henikoff, Steven

doi:10.1016/s1097-2765(02)00542-7

Cited by 1,035 publications

(982 citation statements)

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“…Enrichment of H3.3 has been linked with transcriptional activity and indeed has been proposed to contribute to ensuring that full transcription is maintained through cell division (Ahmad & Henikoff, 2002). However, we recently showed that surprisingly few genes exhibit significantly dysregulated expression in DT40 cells lacking H3.3 (Frey et al , 2014).…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…However, the apparent inconsistency in this idea is merely an extension of an existing paradox. Specifically, HIRA and its orthologs in other species are typically involved in gene silencing and formation of heterochromatin (13,50,64,67,97,116,117,119,123), whereas HIRA's favored deposition substrate, histone H3.3, is linked to transcriptional activation (3,77,80,112,133). However, to our knowledge, histone H3.3 per se has not been shown to directly cause or contribute to transcription activation, and a proportion of histone H3.3 does carry posttranslational marks characteristic of transcriptionally silent chromatin (55,74,77).…”

Section: Chromosome Condensation Is Driven By Histone Chaperones Hiramentioning

confidence: 92%

“…Unfortunately, because human histone H3.3 and canonical H3.1 only differ by 5 amino-acids, differentiating between them immunologically is challenging, making it difficult to ask whether endogenous histone H3.3 is specifically enriched in SAHF. The idea that SAHF contains histone H3.3 may initially seem unlikely, because deposition of histone H3.3 is typically linked to transcription activation (3,77,80,112,133), whereas SAHF is a form of transcriptionally silent facultative heterochromatin (87,88,145). However, the apparent inconsistency in this idea is merely an extension of an existing paradox.…”

Section: Chromosome Condensation Is Driven By Histone Chaperones Hiramentioning

confidence: 99%

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

Adams

2007

Gene

162

135

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Cellular senescence is an important tumor suppression process, and a possible contributor to tissue aging. Senescence is accompanied extensive changes in chromatin structure. In particular, many senescent cells accumulate specialized domains of facultative heterochromatin, called Senescence Associated Heterochromatin Foci (SAHF), which are thought to repress expression of proliferationpromoting genes, thereby contributing to senescence-associated proliferation arrest. This article reviews our current understanding of the structure, assembly and function of these SAHF at a cellular level. The possible contribution of SAHF to tumor suppression and tissue aging is also critically discussed.

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“…This scenario attracted significant attention, raising the questions of whether and to what extent tetramer splitting occurs, at which genomic regions, and during which replication-dependent or -independent processes (1-3, 11). This issue is also affected by the fact that many organisms have distinct H3 variants that are deposited during DNA replication (H3.1) or independently of DNA replication (H3.3) by different deposition machineries (12).A recent analysis, published during the last stages of the present work, showed that all of the canonical H3.1 and most of the variant H3.3 in a human cell line are incorporated by the conservative assembly model, consistent with earlier observations (13). However, a minor fraction of H3.3 is present in mixed old-new tetramers, indicating that tetramer splitting is specific to the H3 variant that incorporates outside of replication.…”

mentioning

confidence: 99%

Splitting of H3–H4 tetramers at transcriptionally active genes undergoing dynamic histone exchange

Katan-Khaykovich

Struhl

2011

Proc. Natl. Acad. Sci. U.S.A.

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Nucleosome deposition occurs on newly synthesized DNA during DNA replication and on transcriptionally active genes via nucleosome-remodeling complexes recruited by activator proteins and elongating RNA polymerase II. It has been long believed that histone deposition involves stable H3-H4 tetramers, such that newly deposited nucleosomes do not contain H3 and H4 molecules with their associated histone modifications from preexisting nucleosomes. However, biochemical analyses and recent experiments in mammalian cells have raised the idea that preexisting H3-H4 tetramers might split into dimers, resulting in mixed nucleosomes composed of "old" and "new" histones. It is unknown to what extent different genomic loci might utilize such a mechanism and under which circumstances. Here, we address whether tetramer splitting occurs in a locus-specific manner by using sequential chromatin immunoprecipitation of mononucleosomes from yeast cells containing two differentially tagged versions of H3 that are expressed "old" and "new" histones. At many genomic loci, we observe little or no nucleosomal cooccupancy of old and new H3, indicating that tetramer splitting is generally infrequent. However, cooccupancy is detected at highly active genes, which have a high rate of histone exchange. Thus, DNA replication largely results in nucleosomes bearing exclusively old or new H3-H4, thereby precluding the acquisition of new histone modifications based on preexisting modifications within the same nucleosome. In contrast, tetramer splitting, dimer exchange, and nucleosomes with mixed H3-H4 tetramers occur at highly active genes, presumably linked to rapid histone exchange associated with robust transcription.T he packaging of eukaryotic DNA into chromatin influences many DNA-associated processes, including transcriptional regulation. Within the chromatin fiber, each basic nucleosome unit bears important chemical and structural information. The mechanisms by which nucleosomes are assembled on DNA during replication, transcription, DNA repair, etc., can thus impact not only the integrity of chromatin structure but also patterns of gene expression and epigenetic inheritance. The H3-H4 tetramer core of each nucleosome is the more stable component and contains most of the relatively persistent and functionally important histone methylation marks. Much attention has therefore been given to the questions of how the H3-H4 tetramers are formed and maintained on chromatin.Early studies attempted to distinguish between a conservative assembly model, by which old and new histones form separate tetramers on replicating DNA, and a semiconservative assembly mechanism, by which existing tetramers are split into H3-H4 dimers, followed by association of new H3-H4 dimers to complete each nucleosome core (1-3). In the semiconservative model, the resulting tetramers would bear a mixture of old and new histones, allowing transmission of epigenetic information within the basic nucleosome unit. Though mechanistically attractive, the mixed tetramer model receiv...

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The Histone Variant H3.3 Marks Active Chromatin by Replication-Independent Nucleosome Assembly

Cited by 1,035 publications

References 61 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

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

Splitting of H3–H4 tetramers at transcriptionally active genes undergoing dynamic histone exchange

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