MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Marjanović, Melanija Posavec; Hurtado-Bagès, Sarah; Lassi, Maximilian; Valero, Vanesa; Malinverni, Roberto; Delage, Hélène; Navarro, Míriam Guillén; Corujo, David; Guberović, Iva; Douet, Julien; Gama-Pérez, Pau; García-Rovés, Pablo M.; Ahel, Ivan; Ladurner, Andreas G.; Yanes, Óscar; Bouvet, Philippe; Suelves, Mònica; Teperino, Raffaele; Pospisilik, J. Andrew; Buschbeck, Marcus

doi:10.1038/nsmb.3481

Cited by 52 publications

(63 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar observations have been reported in Wk4 hPGCs and D4 hPGCLCs (Gell et al, 2020;Gkountela et al, 2013;Gomes Fernandes et al, 2018;Tang et al, 2015). By contrast, mouse PGCs show persistent H3K27me3 in gonadal PGCs (de Sousa Lopes et al, 2008;Seki et al, 2005), which might have a role in maintaining genomic integrity during the period of active DNA demethylation (Cotton et al, 2013 Posavec Marjanović et al, 2017 ). Interestingly, we found high PARP1 levels in pre-migratory and gonadal PGCs ( Fig.…”

Section: Dynamic Chromatin Changes In Ppgcsupporting

confidence: 89%

Specification and epigenetic resetting of the pig germline exhibit conservation with the human lineage

Zhu

Sang²,

Withey

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryInvestigations on the human germline and programming are challenging due to limited access to embryonic material. However, the pig as a model may provide insight on transcriptional network and epigenetic reprogramming applicable to both species. Here we show that during the pre- and early migratory stages pig primordial germ cells (PGCs) initiate large-scale epigenetic reprogramming, including DNA demethylation involving TET-mediated hydroxylation and potentially base excision repair (BER). There is also macroH2A1 depletion and increased H3K27me3, as well as X chromosome reactivation (XCR) in females. Concomitantly, there is dampening of glycolytic metabolism genes and re-expression of some pluripotency genes like those in preimplantation embryos. We identified evolutionarily young transposable elements and gene coding regions resistant to DNA demethylation in acutely hypomethylated gonadal PGCs, with potential for transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute significantly to advances in human germline biology, including in vitro gametogenesis.

show abstract

Section: Dynamic Chromatin Changes In Ppgcsupporting

confidence: 89%

Specification and epigenetic resetting of the pig germline exhibit conservation with the human lineage

Zhu

Sang²,

Withey

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Here, we find that macroH2A1.1 levels are particularly high in post‐mitotic Sertoli cells in the testis, for example, while the splice variant macroH2A1.2 is also expressed in highly proliferative lymphocytes forming the inner lymph node (Fig EV1C). Further, during myogenic differentiation, which is associated with cell cycle exit, the splicing of the primary macroH2A1 transcript switches from macroH2A1.2 to the macroH2A1.1 isoform .…”

Section: Resultsmentioning

confidence: 99%

“…Our previous structural analysis of the macroH2A1.1 macrodomain in complex with monomeric ADP‐ribose revealed that this macrodomain module engages ADP‐ribose in a manner that would allow macroH2A1.1 to cap oligo‐ADP‐ribose chains as PARP1 synthesizes them on PARP1 targets . We hypothesized that such a molecular “capping” function might be essential for the known capacity of macroH2A1.1 to both bind and inhibit auto‐modified PARP1 . Some controversy exists on whether other macrodomain modules, and in particular the macrodomain of the distinct macroH2A2 histone isoform, can inhibit PARP1 activity .…”

Section: Resultsmentioning

confidence: 99%

“…When inducing DNA damage in our cell lines, we find that macroH2A1.1 reduced chromatin expansion, while overexpression of canonical H2A did not (Fig C). Mutation of a key residue (G224E) in the ADP‐ribose binding pocket of macroH2A1.1 eliminates the binding of ADP‐ribose and abrogates PARP1 binding and inhibition .…”

Section: Resultsmentioning

confidence: 99%

“…Depending on the cellular context, this can lead to PARP1 recruitment and gene regulation or the inhibition of basal PARP1 activity . In muscle cells, the latter globally impacts cellular NAD + metabolism , revealing an important metabolic function for macroH2A1.1.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms

et al. 2018

Self Cite

View full text Add to dashboard Cite

MacroH2A histone variants suppress tumor progression and act as epigenetic barriers to induced pluripotency. How they impart their influence on chromatin plasticity is not well understood. Here, we analyze how the different domains of macroH2A proteins contribute to chromatin structure and dynamics. By solving the crystal structure of the macrodomain of human macroH2A2 at 1.7 Å, we find that its putative binding pocket exhibits marked structural differences compared with the macroH2A1.1 isoform, rendering macroH2A2 unable to bind ADP-ribose. Quantitative binding assays show that this specificity is conserved among vertebrate macroH2A isoforms. We further find that macroH2A histones reduce the transient, PARP1-dependent chromatin relaxation that occurs in living cells upon DNA damage through two distinct mechanisms. First, macroH2A1.1 mediates an isoform-specific effect through its ability to suppress PARP1 activity. Second, the unstructured linker region exerts an additional repressive effect that is common to all macroH2A proteins. In the absence of DNA damage, the macroH2A linker is also sufficient for rescuing heterochromatin architecture in cells deficient for macroH2A.

show abstract

Therapeutic Potentials of Poly (ADP‐Ribose) Polymerase 1 (PARP1) Inhibition in Multiple Sclerosis and Animal Models: Concept Revisiting

et al. 2021

View full text Add to dashboard Cite

Poly (ADP-ribose) polymerase 1 (PARP1) plays a fundamental role in DNA repair and gene expression. Excessive PARP1 hyperactivation, however, has been associated with cell death. PARP1 and/or its activity are dysregulated in the immune and central nervous system of multiple sclerosis (MS) patients and animal models. Pharmacological PARP1 inhibition is shown to be protective against immune activation and disease severity in MS animal models while genetic PARP1 deficiency studies reported discrepant results. The inconsistency suggests that the function of PARP1 and PARP1-mediated PARylation may be complex and context-dependent. The article reviews PARP1 functions, discusses experimental findings and possible interpretations of PARP1 in inflammation, neuronal/axonal degeneration, and oligodendrogliopathy, three major pathological components cooperatively determining MS disease course and neurological progression, and points out future research directions. Cell type specific PARP1 manipulations are necessary for revisiting the role of PARP1 in the three pathological components prior to moving PARP1 inhibition into clinical trials for MS therapy.

show abstract

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Cited by 52 publications

References 52 publications

Specification and epigenetic resetting of the pig germline exhibit conservation with the human lineage

Specification and epigenetic resetting of the pig germline exhibit conservation with the human lineage

MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms

Therapeutic Potentials of Poly (ADP‐Ribose) Polymerase 1 (PARP1) Inhibition in Multiple Sclerosis and Animal Models: Concept Revisiting

Contact Info

Product

Resources

About