Flore Mietton

Centre National de la Recherche Scientifique

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Jérôme Govin

Institut pour l'avancée des biosciences

Carlo Petosa

Université Grenoble Alpes

B. A. Kashemirov

University of Southern California

Muriel Cornet

Université Grenoble Alpes

Morgane Champleboux

Centre National de la Recherche Scientifique

Cécile Garnaud

Centre Hospitalier Universitaire de Grenoble

Danièle Maubon

Translational Innovation in Medicine and Complexity

Ninon Zala

Institut de Biologie Structurale

Mitchell Hull

Scripps (United States)

Marie Courçon

Inserm

Cooperative Institutions

Centre National de la Recherche Scientifique

Inserm

Université Grenoble Alpes

Institut pour l'avancée des biosciences

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

CEA Grenoble

Université Joseph Fourier

Institut de Biosciences et Biotechnologies

Centre Hospitalier Universitaire de Grenoble

Université Claude Bernard Lyon 1

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Nucleolin is a histone chaperone with FACT-like activity and assists remodeling of nucleosomes

The EMBO Journal (2006)

Dimitar Angelov V. A. Bondarenko Sébastien Almagro Hervé Menoni Fabien Mongélard

Nucleolin

Chaperone (clinical)

10.1038/sj.emboj.7601046

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Citations (246)

The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity

Genes & Development (2006)

Khalid Ouararhni Réda Hadj-Slimane Slimane Ait‐Si‐Ali Philippe Robin Flore Mietton

The histone variant mH2A is believed to be involved in transcriptional repression, but how it exerts its function remains elusive. By using chromatin immunoprecipitation and tandem affinity immunopurification of the mH2A1.1 nucleosome complex, we identified numerous genes with promoters containing mH2A1.1 nucleosomes. In particular, the promoters of the inducible Hsp70.1 and Hsp70.2 genes, but not that of the constitutively expressed Hsp70.8 , were highly enriched in mH2A1.1. PARP-1 was identified as a part of the mH2A1.1 nucleosome complex and was found to be associated with the Hsp70.1 promoter. A specific interaction between mH2A1.1 and PARP-1 was demonstrated and found to be associated with inactivation of PARP-1 enzymatic activity. Heat shock released both mH2A1.1 and PARP-1 from the Hsp70.1 promoter and activated PARP-1 automodification activity. The data we present point to a novel mechanism for control of Hsp70.1 gene transcription. mH2A1.1 recruits PARP-1 to the promoter, thereby inactivating it. Upon heat shock, the Hsp70.1 promoter-bound PARP-1 is released to activate transcription through ADP-ribosylation of other Hsp70.1 promoter-bound proteins.

Chromatin immunoprecipitation

Transcription

10.1101/gad.396106

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Citations (163)

Mechanism of Polymerase II Transcription Repression by the Histone Variant macroH2A

Molecular and Cellular Biology (2006)

Cécile-Marie Doyen Woojin An Dimitar Angelov Vоlodymyr Bondarenko Flore Mietton

macroH2A (mH2A) is an unusual histone variant consisting of a histone H2A-like domain fused to a large nonhistone region. In this work, we show that histone mH2A represses p300- and Gal4-VP16-dependent polymerase II transcription, and we have dissected the mechanism by which this repression is realized. The repressive effect of mH2A is observed at the level of initiation but not at elongation of transcription, and mH2A interferes with p300-dependent histone acetylation. The nonhistone region of mH2A is responsible for both the repression of initiation of transcription and the inhibition of histone acetylation. In addition, the presence of this domain of mH2A within the nucleosome is able to block nucleosome remodeling and sliding of the histone octamer to neighboring DNA segments by the remodelers SWI/SNF and ACF. These data unambiguously identify mH2A as a strong transcriptional repressor and show that the repressive effect of mH2A is realized on at least two different transcription activation chromatin-dependent pathways: histone acetylation and nucleosome remodeling.

Histone octamer

Histone code

Histone Methylation

10.1128/mcb.26.3.1156-1164.2006

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Citations (141)

Second Bromodomain (BD2) from Candida albicans Bdf1 in the unbound form

Flore Mietton Elías Fernando Rodríguez Ferri M. Champlebouxm Ninon Zala Danièle Maubon

10.2210/pdb5n13/pdb

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First Bromodomain (BD1) from Candida albicans Bdf1 bound to a dibenzothiazepinone (compound 1)

Flore Mietton Elías Fernando Rodríguez Ferri Morgane Champleboux Ninon Zala Danièle Maubon

10.2210/pdb5n16/pdb

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Weak but Uniform Enrichment of the Histone Variant macroH2A1 along the Inactive X Chromosome

Molecular and Cellular Biology (2008)

Flore Mietton Aditya K. Sengupta Annie Molla Gisele Fernanda Assine Picchi Sophie Barral

We studied the enrichment and distribution of the histone variant mH2A1 in the condensed inactive X (Xi) chromosome. By using highly specific antibodies against mH2A1 and stable HEK 293 cell lines expressing either green fluorescent protein (GFP)-mH2A1 or GFP-H2A, we found that the Xi chromosome contains ∼1.5-fold more mH2A1 than the autosomes. To determine the in vivo distribution of mH2A1 along the X chromosome, we used a native chromatin immunoprecipitation-on-chip technique. DNA isolated from mH2A1-immunoprecipitated nucleosomes from either male or female mouse liver were hybridized to tiling microarrays covering 5 kb around most promoters or the entire X chromosome. The data show that mH2A1 is uniformly distributed across the entire Xi chromosome. Interestingly, a stronger mH2A1 enrichment along the pseudoautosomal X chromosome region was observed in both sexes. Our results indicate a potential role for macroH2A in large-scale chromosome structure and genome stability.

Chromatin immunoprecipitation

Pseudoautosomal region

10.1128/mcb.00997-08

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Citations (57)

A Large Fraction of Extragenic RNA Pol II Transcription Sites Overlap Enhancers

PLoS Biology (2010)

Francesca De Santa Iros Barozzi Flore Mietton Serena Ghisletti Sara Polletti

Mammalian genomes are pervasively transcribed outside mapped protein-coding genes. One class of extragenic transcription products is represented by long non-coding RNAs (lncRNAs), some of which result from Pol_II transcription of bona-fide RNA genes. Whether all lncRNAs described insofar are products of RNA genes, however, is still unclear. Here we have characterized transcription sites located outside protein-coding genes in a highly regulated response, macrophage activation by endotoxin. Using chromatin signatures, we could unambiguously classify extragenic Pol_II binding sites as belonging to either canonical RNA genes or transcribed enhancers. Unexpectedly, 70% of extragenic Pol_II peaks were associated with genomic regions with a canonical chromatin signature of enhancers. Enhancer-associated extragenic transcription was frequently adjacent to inducible inflammatory genes, was regulated in response to endotoxin stimulation, and generated very low abundance transcripts. Moreover, transcribed enhancers were under purifying selection and contained binding sites for inflammatory transcription factors, thus suggesting their functionality. These data demonstrate that a large fraction of extragenic Pol_II transcription sites can be ascribed to cis-regulatory genomic regions. Discrimination between lncRNAs generated by canonical RNA genes and products of transcribed enhancers will provide a framework for experimental approaches to lncRNAs and help complete the annotation of mammalian genomes.

Transcription

Enhancer RNAs

RNA polymerase II

10.1371/journal.pbio.1000384

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Citations (834)

Localisation et fonction du variant d'histone macroH2A

Flore Mietton

La structure de la chromatine et sa compaction sont modulees par la substitution des histones conventionnelles par des variants d'histones. MacroH2A est l'un de ces variants et se singularise par sa grande taille. De nombreuses donnees suggerent que macroH2A pourrait participer a l'inactivation de la transcription. Par immunofluorescence, cette proteine est retrouvee accumulee sur le territoire du chromosome X inactif (Xi) chez les mammiferes femelles. Neanmoins, cette association preferentielle pourrait simplement refleter la forte concentration en nucleosomes de cette region. Pour aborder le role de macroH2A dans le phenomene de l'inactivation du chromosome X, notre principale approche a consiste en des experiences de «ChIP-on-CHIP» sur de la chromatine native. Nos resultats montrent un enrichissement global et modeste de macroH2A sur le chromosome X femelle, excepte sur la plupart des genes echappant a l'inactivation. Nous avons souhaite nous interesser egalement au role potentiel de macroH2A dans le mecanisme de reparation de l'ADN. En effet, il a ete montre que le domaine macro est capable de lier l'ADP-ribose, un nucleotide determinant dans de nombreux processus biologiques tels que la transcription ou la reparation. Plusieurs experiences nous ont permis de demontrer que les nucleosomes macroH2A sont associes in vivo a l'enzyme P ARP-l, proteine clef de la reparation des cassures simple brin de l'ADN. La P ARP-l associee au nucleosome variant est inactive, et le traitement par H202 va induire son relâchement et son activation. L'absence de macroH2A conduit a une sur-activation de P ARP-l, ce qui compromet severement la reparation de l'ADN endommage.

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Exploring the antifungal potential of Bdf1 bromodomain inhibitors

Acta Crystallographica Section A Foundations and Advances (2024)

Kevin Wei Marie Arlotto Justin M. Overhulse Timothy A. Dinh Yujie Zhou

10.1107/s2053273324098504

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Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Nature Communications (2017)

Flore Mietton Elena Ferri Morgane Champleboux Ninon Zala Danièle Maubon

Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

Phenocopy

BRD4

10.1038/ncomms15482

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Citations (45)