MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms

Kozłowski, Marek; Corujo, David; Hothorn, Michael; Guberović, Iva; Mandemaker, Imke K.; Blessing, Charlotte; Sporn, Judith C.; Gutierrez‐Triana, Arturo; Smith, Rebecca; Portmann, Thomas; Treier, Mathias; Scheffzek, Klaus; Huet, Sébastien; Timinszky, Gyula; Buschbeck, Marcus; Ladurner, Andreas G.

doi:10.15252/embr.201744445

Cited by 68 publications

(63 citation statements)

References 60 publications

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“…Furthermore, only macroH2A.1.1 suppresses PARP1 activity, preventing the formation of an open chromatin structure. By contrast, all three histone variants of macroH2A (macroH2A.1.1, macroH2A.1.2 and macroH2A.2) retain the ability to stabilise condensed chromatin structure via their common linker region [115]. Subsequently, macroH2A.1.1 participates in recognizing and binding PAR chains to inactivate PARP1 ( Figure 4C), whereas the linker region, being present in all three isoforms, may play an additional role in chromatin compaction.…”

Section: Parylation In the Regulation Of Dna Damage-induced Chromatinmentioning

confidence: 99%

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

Páhi

Borsos

Pantazi

et al. 2020

Cancers

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Transcription is a multistep, tightly regulated process. During transcription initiation, promoter recognition and pre-initiation complex (PIC) formation take place, in which dynamic recruitment or exchange of transcription activators occur. The precise coordination of the recruitment and removal of transcription factors, as well as chromatin structural changes, are mediated by post-translational modifications (PTMs). Poly(ADP-ribose) polymerases (PARPs) are key players in this process, since they can modulate DNA-binding activities of specific transcription factors through poly-ADP-ribosylation (PARylation). PARylation can regulate the transcription at three different levels: (1) by directly affecting the recruitment of specific transcription factors, (2) by triggering chromatin structural changes during initiation and as a response to cellular stresses, or (3) by post-transcriptionally modulating the stability and degradation of specific mRNAs. In this review, we principally focus on these steps and summarise the recent findings, demonstrating the mechanisms through which PARylation plays a potential regulatory role during transcription and DNA repair.

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Section: Parylation In the Regulation Of Dna Damage-induced Chromatinmentioning

confidence: 99%

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

Páhi

Borsos

Pantazi

et al. 2020

Cancers

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“…Interestingly, PARP1 and macroH2A1.2 have opposing effects on chromatin structure. PARP1 and PARylation decompacts chromatin while macroH2A1 compacts chromatin, including through a mechanism involving PAR binding by the macrodomain of macroH2A1.1 (Khurana et al, 2014;Kozlowski et al, 2018;Krishnakumar and Kraus, 2010;Timinszky et al, 2009). macroH2A1.2 lacks a PAR-binding macrodomain but recent evidence has shown that this variant is still able to compact chromatin through an activity located in the linker region (Kozlowski et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…We focused on the histone variant macroH2A as this variant can bind and be regulated by PARP and is involved in HR (Khurana et al, 2014;Ruiz et al, 2019;Timinszky et al, 2009). macroH2A1 has two splice variants, macroH2A1.1 and macroH2A1.2, which differ in 32 amino acids within the C-terminal macrodomain leading to the presence of a PAR binding domain in macroH2A1.1 but not in macroH2A1.2 (Kozlowski et al, 2018;Timinszky et al, 2009). macroH2A2 is expressed from a second, independent gene and does not bind to PAR but is ~80% identical with macroH2A1 (Posavec et al, 2013).…”

Section: Kdm5a Interacts With the Histone Variant Macroh2a1mentioning

confidence: 99%

Poly(ADP-ribose)-binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions

Kumbhar

Perren

Gong

et al. 2020

Preprint

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The histone demethylase KDM5A removes histone H3 lysine 4 methylation, which is involved in transcription and DNA damage responses (DDR). While DDR functions of KDM5A have been identified, how KDM5A recognizes DNA lesion sites within chromatin is unknown. Here, we identify two factors that act upstream of KDM5A to promote its association with DNA damage sites. We have identified a non-canonical poly(ADP-ribose), (PAR), binding region unique to KDM5A. Loss of the PAR-binding region or treatment with PAR polymerase (PARP) inhibitors (PARPi) blocks KDM5A-PAR interactions and DNA repair functions of KDM5A. The histone variant macroH2A1.2 is also specifically required for KDM5A recruitment and functions at DNA damage sites, including homology-directed repair of DNA double-strand breaks and repression of transcription at DNA breaks. Overall, this work reveals the importance of PAR-binding and macroH2A1.2 in KDM5A recognition of damage sites that drive transcriptional and repair activities at DNA breaks within chromatin that are essential for maintaining genome integrity.SummaryThe histone demethylase KDM5A demethylates H3K4 to promote repair and transcriptional responses at DNA breaks. We identified poly(ADP-ribose)-binding and macroH2A1.2 as modulators of KDM5A association with DNA damage sites, revealing how KDM5A engages DNA breaks within chromatin.

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“…In stickleback, we found multiple genes coding for H2A variants such as H2Afv, while only one gene codes for macroH2A that can give rise to three isoforms. This differs from mammals, where macroH2A was duplicated and gives rise to three isoforms (2 proteins gene 1, 1 protein gene 2) (Kozlowski et al, 2018). This, in conjunction with its duplication in a number of fish species, suggests potential teleost-specific biological functions.…”

Section: Stickleback H2amentioning

confidence: 91%

“…This, in conjunction with its duplication in a number of fish species, suggests potential teleost-specific biological functions. Furthermore, in our opinion, macroH2A might be of particular interest for eco-evolutionary studies as it has been linked to embryonic defects in mouse and zebrafish (Kozlowski et al, 2018), and is essential to cold acclimation in fish (Pinto et al, 2005).…”

Section: Stickleback H2amentioning

confidence: 96%

Genome Survey of Chromatin-Modifying Enzymes in Threespine Stickleback: A Crucial Epigenetic Toolkit for Adaptation?

Fellous

Shama

2019

Front. Mar. Sci.

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Ocean environments are changing rapidly and marine organisms need to cope with these changes in order to survive, develop, and reproduce. To do so, organisms can either migrate, adapt in situ or acclimate via phenotypic plasticity. In this context, the emerging field of environmental epigenetics investigates the contribution of genetic and epigenetic information to adaptive potential of wild populations. Epigenetic modifications are based on the highly dynamic combination of DNA methylation, histone modifications, and non-coding RNAs, which may facilitate phenotypic plasticity through genotype-epigenotype-environment interactions, and can drive rapid evolution in wild populations. However, while knowledge of epigenetic contributions to phenotypes across different developmental and generational timescales is increasing for medical research model species, the mechanistic and synergistic action of these modifications remain comparatively understudied in ecological models such as teleost fishes. Here, we characterized the evolution of the gene toolkit involved in key molecular epigenetic pathways including DNA methylation, histone modifications, macroH2A histone, and miRNA biogenesis/turnover in threespine stickleback, a model species in evolution and ecology. We then investigated these genes within a phylogenetic context by comparing them in stickleback to human, mouse, chicken, tropical clawed frog, zebrafish, medaka, green spotted puffer, channel catfish, and mangrove rivulus. We found that, in general, conserved domains, in conjunction with their phylogenetic positions, suggest evolutionary conservation of putative enzyme activity in stickleback. However, molecular epigenetic pathways also revealed that teleost gene evolution is diversified and complex. Specifically, the number of genes, gene loss/duplication events, identified conserved domains, and putative protein lengths vary greatly from one species to another, particularly within fishes, which exhibit a potentially new class of histone deacetylases. This suggests different biological functions specific to fish species, and that the action of genes regulating epigenetic modifications in model species are not necessarily applicable to other related species. We integrate our results into recent advances concerning epigenetic mechanisms in teleosts, and conclude by discussing the necessity to delve deeper into the fundamental mechanics of epigenetic modifications in a wide array of taxa, particularly those relevant for assisted evolution, conservation, aquaculture, fisheries, and climate change-adaptation studies.

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MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms

Cited by 68 publications

References 60 publications

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

Poly(ADP-ribose)-binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions

Genome Survey of Chromatin-Modifying Enzymes in Threespine Stickleback: A Crucial Epigenetic Toolkit for Adaptation?

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