DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network

Carraro, Massimo; Hendriks, Ivo A.; Hammond, Colin M.; Solis‐Mezarino, Victor; Völker-Albert, Moritz; Elsborg, Jonas D.; Weisser, Melanie; Spanos, Christos; Montoya, Guillermo; Rappsilber, Juri; Imhof, Axel; Nielsen, Michael L.; Groth, Anja

doi:10.1016/j.molcel.2023.02.009

Cited by 32 publications

(23 citation statements)

References 127 publications

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“…In contrast, the observed derepression of genes and LTR-type retroposons in heterochromatic regions provides strong evidence that H3.3K36 is involved in maintaining repressive pericentric and subtelomeric chromatin, possibly through ATRX•Daxx-mediated deposition. Consistent with these observations, Groth and colleages have recently shown that DAXX provides additional functionality to the histone chaperone system by recruiting H3K9 methyltransferases [78]. Even more recently, the same group showed that a failure to re-establish H3K9me in post-replicative mammalian chromatin causes derepression of LTR-type retroposons [79].…”

Section: Discussionmentioning

confidence: 83%

Lysine-36 ofDrosophilahistone H3.3 supports adult longevity

Brown,

McMichael,

Vandadi

et al. 2023

Preprint

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Aging is a multifactorial process that disturbs homeostasis, increases disease susceptibility, and ultimately results in death. Although the definitive set of molecular mechanisms responsible for aging remain to be discovered, epigenetic change over time is proving to be a promising piece of the puzzle. Several posttranslational histone modifications (PTMs) have been linked to the maintenance of longevity. Here, we focus on lysine 36 of the replication- independent histone protein, H3.3 (H3.3K36). To interrogate the role of this residue inDrosophiladevelopmental gene regulation, we generated a lysine to arginine mutant that blocks the activity of its cognate modifying enzymes. We found that anH3.3BK36Rmutation causes a significant reduction in adult lifespan, accompanied by dysregulation of the genomic and transcriptomic architecture. Transgenic co-expression of wild-typeH3.3Bcompletely rescues the longevity defect. Because H3.3 is known to accumulate in non- dividing tissues, we carried out transcriptome profiling of young vs aged adult fly heads. The data show that loss of H3.3K36 results in age-dependent misexpression of NF-κB and other innate immune target genes, as well as defects in silencing of heterochromatin. We propose H3.3K36 maintains the postmitotic epigenomic landscape, supporting longevity by regulating both pericentric and telomeric retrotransposition and by suppressing aberrant immune signaling.

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Section: Discussionmentioning

confidence: 83%

Lysine-36 ofDrosophilahistone H3.3 supports adult longevity

Brown,

McMichael,

Vandadi

et al. 2023

Preprint

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“…The nature of this replication-independent effect of CAF-1 remains unclear, with possible local contributions to the slowdown of replication forks in late S-phase. It will be important to shed light on these mechanisms, and the possible involvement of the de novo deposition of H3.3K9me3 87,88 . Indeed, we did not observe significant changes upon CAF-1 loss in H3K9me3 marks at the domain-level using ChiC-seq.…”

Section: Epigenome Instability Upon Caf-1 Loss: Different Effects In ...mentioning

confidence: 99%

Acute multi-level response to defective de novo chromatin assembly in S-phase

Dreyer,

Ricci,

van den Berg

et al. 2024

Preprint

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Long-term perturbation of de novo chromatin assembly during DNA replication has profound effects on epigenome maintenance and cell fate. The early mechanistic origin of these defects is unknown. Here, we combine acute degradation of Chromatin Assembly Factor 1 (CAF-1), a key player in de novo chromatin assembly, with single-cell genomics, quantitative proteomics, and live-microscopy to uncover these initiating mechanisms in human cells. CAF-1 loss immediately slows down DNA replication speed and renders nascent DNA hyper-accessible. A rapid cellular response, distinct from canonical DNA damage signaling, is triggered and lowers histone mRNAs. As a result, histone variants usage and their modifications are altered, limiting transcriptional fidelity and delaying chromatin maturation within a single S-phase. This multi-level response induces a cell-cycle arrest after mitosis. Our work reveals the immediate consequences of defective de novo chromatin assembly during DNA replication, explaining how at later times the epigenome and cell fate can be altered.

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“…These data suggest that human SPT2 can regulate H3–H4 function, at least in yeast, but similar roles in human cells have not yet been described. More recent work has shown by molecular modeling that SPT2 can also co-chaperone a histone H3–H4 dimer together with ASF1A 33 .…”

Section: Mainmentioning

confidence: 99%

The histone chaperone SPT2 regulates chromatin structure and function in Metazoa

Saredi,

Carelli,

Rolland

et al. 2024

Nat Struct Mol Biol

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Histone chaperones control nucleosome density and chromatin structure. In yeast, the H3–H4 chaperone Spt2 controls histone deposition at active genes but its roles in metazoan chromatin structure and organismal physiology are not known. Here we identify the Caenorhabditis elegans ortholog of SPT2 (CeSPT-2) and show that its ability to bind histones H3–H4 is important for germline development and transgenerational epigenetic gene silencing, and that spt-2 null mutants display signatures of a global stress response. Genome-wide profiling showed that CeSPT-2 binds to a range of highly expressed genes, and we find that spt-2 mutants have increased chromatin accessibility at a subset of these loci. We also show that SPT2 influences chromatin structure and controls the levels of soluble and chromatin-bound H3.3 in human cells. Our work reveals roles for SPT2 in controlling chromatin structure and function in Metazoa.

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DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network

Cited by 32 publications

References 127 publications

Lysine-36 ofDrosophilahistone H3.3 supports adult longevity

Lysine-36 ofDrosophilahistone H3.3 supports adult longevity

Acute multi-level response to defective de novo chromatin assembly in S-phase

The histone chaperone SPT2 regulates chromatin structure and function in Metazoa

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