An embryonic stem cell-specific heterochromatin state allows core histone exchange in the absence of DNA accessibility

Navarro, Carmen; Elsässer, Simon J.

doi:10.1101/2020.05.22.110742

Cited by 4 publications

(3 citation statements)

References 61 publications

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“…1a, b). ATRX-enriched regions were often enriched with the histone variant, H3.3, and with H3K9me3, consistent with previous reports of this unique class of heterochromatin in ESCs 11,28 (Fig. 1a).…”

Section: Resultssupporting

confidence: 91%

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

et al. 2021

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ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

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Section: Resultssupporting

confidence: 91%

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

et al. 2021

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show abstract

“…1a, 1b). ATRX-enriched regions were often enriched with the histone variant, H3.3, and with H3K9me3, consistent with previous reports of this unique class of heterochromatin in ESCs 11,28 (Fig. 1a).…”

Section: Atrx Associates With G4 Structures In Vivosupporting

confidence: 91%

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

Teng

Sundaresan

O’Hara

et al. 2021

Preprint

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ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with the MCM replication complex and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

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“…In contrast to the considerable sequence differences between H2A.Z and H2A, H3.3 differs from replication-coupled H3 by only a few amino acids and H3.3 containing nucleosomes are essentially structurally identical to H3 containing nucleosomes [49]. Regardless, many studies show that regions enriched with H3.3 undergo more dynamic nucleosome exchange than other regions of the genome [50][51][52][53][54][55][56]. While these results might suggest that H3.3 is required to maintain chromatin accessibility at enhancers, nucleosome occupancy at regulatory elements does not change and chromatin does not become less accessible at enhancers in ESCs lacking H3.3 [53,57].…”

Section: H33mentioning

confidence: 99%

Establishment and function of chromatin modification at enhancers

Tafessu

Banaszynski

2020

Open Biol.

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How a single genome can give rise to distinct cell types remains a fundamental question in biology. Mammals are able to specify and maintain hundreds of cell fates by selectively activating unique subsets of their genome. This is achieved, in part, by enhancers—genetic elements that can increase transcription of both nearby and distal genes. Enhancers can be identified by their unique chromatin signature, including transcription factor binding and the enrichment of specific histone post-translational modifications, histone variants, and chromatin-associated cofactors. How each of these chromatin features contributes to enhancer function remains an area of intense study. In this review, we provide an overview of enhancer-associated chromatin states, and the proteins and enzymes involved in their establishment. We discuss recent insights into the effects of the enhancer chromatin state on ongoing transcription versus their role in the establishment of new transcription programmes, such as those that occur developmentally. Finally, we highlight the role of enhancer chromatin in new conceptual advances in gene regulation such as condensate formation.

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An embryonic stem cell-specific heterochromatin state allows core histone exchange in the absence of DNA accessibility

Cited by 4 publications

References 61 publications

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

Establishment and function of chromatin modification at enhancers

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