Four enzymes cooperate to displace histone H1 during the first minute of hormonal gene activation

Vicent, Guillermo P.; Nacht, A. Silvina; Font-Mateu, Jofre; Castellano, Giancarlo; Gaveglia, Laura; Ballaré, Cecilia; Beato, Miguel

doi:10.1101/gad.621811

Cited by 102 publications

(130 citation statements)

References 87 publications

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“…HMGA proteins were shown to dynamically compete with H1 for binding to the linker DNA, thereby loosening the chromatin [30,31]. In addition, displacement of H1 during the initial steps of gene activation has been reported [32]. Furthermore, the histone chaperone complex FACT (facilitates chromatin transcription) catalyzes integration of H2AX into nucleosomes [33], induces disassembly of promoter-associated nucleosomes, and enhances transcriptional activation [34].…”

Section: Discussionmentioning

confidence: 99%

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

et al. 2015

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The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFβ1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome.

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Section: Discussionmentioning

confidence: 99%

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

et al. 2015

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“…ChIP was performed as previously described (37,38). Antibodies and PCR primers used in this assay are reported in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

Caizzi

Ferrero

Cutrupi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Estrogen receptor-α (ERα) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ERα has functions that are independent of ligands. In the present work, we investigated the binding of ERα to chromatin in the absence of ligands and its functions on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ERα binds to more than 4,000 chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ERα binding is specifically linked to genes with developmental functions, compared with estrogen-induced binding. Moreover, we found that siRNA-mediated down-regulation of ERα in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Down-regulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ERα down-regulation using shRNA, which caused cell growth arrest, was accompanied by increased H3K27me3 at ERα binding sites. Finally, we found that FOXA1 and AP2γ binding to several sites is decreased upon ERα silencing, suggesting that unliganded ERα participates, together with other factors, in the maintenance of the luminal-specific cistrome in breast cancer cells.

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“…7 Already one minute after hormone treatment pPR interacts with and activates the CyclinA/CDK2 complex, which is recruited to regulated promoters and phosphorylates histone H1. 8 Hormone activated CDK2 also phosphorylates poly (ADP-ribose) polymerase 1 (PARP1), which converts NAD+ to poly(ADP-ribose) (PAR) attached to itself and to linker and core histones, facilitating displacement of histone H1. 9 This initial remodeling step requires also NURF, an ATP-dependent chromatin remodeling complex that is recruited to target sites via interaction with PR and is stabilized by trimethylation of histone H3 at lysine 4 catalyzed by MLL2/3 of the ASCOM complex.…”

Section: Pr Binding Sites Are Marked By High Nucleosomes Occupancymentioning

confidence: 99%

More help than hindrance

Ballaré

Zaurín

Vicent

et al. 2013

Nucleus

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a major challenge of modern human biology is to understand how a differentiated somatic cell integrates the response to external signals in the complex context of basic metabolic and tissuespecific gene expression programs. this requires exploring two interconnected basic processes: the signaling network and the global function of the key transcription factors on which signaling acts to modulate gene expression. an apparently simple model to study these questions has been steroid hormones action, since their intracellular receptors both initiate signaling and are the key transcription factors orchestrating the cellular response. we have used progesterone action in breast cancer cells to elucidate the intricacies of progesterone receptor (pr) signaling crosstalk with protein kinases, histone modifying enzymes and atp-dependent chromatin remodeling complexes. 1 recently we have described the cistrome of pr in these cells at different times after addition of hormone and its relationship to chromatin structure.2 the role of chromatin in transcription factor binding to the genome is still debated, but the dominant view is that factors bind preferentially to nucleosome-depleted regions, usually identified as dnasei-hypersensitive sites (dhs). in contrast with this vision, we have shown that pr requires nucleosomes for optimal binding and function. in breast cancer cells treated with progestins we identified 25,000 pr binding sites (prbs), the majority encompassing several copies of the hexanucleotide tgtyCy, highly abundant in the genome. we found that strong functional prbs accumulate more help than hindrance Nucleosomes aid transcriptional regulation Cecilia Ballaré, Roser Zaurin, Guillermo P. Vicent and Miguel Beato* Gene Regulation Stem Cells and Cancer Program; Centre for Genomic Regulation (CRG); Barcelona, Spain; University Pompeu Fabra (UPF); Barcelona, Spain around progesterone-induced genes mainly in enhancers, are enriched in dhs but exhibit high nucleosome occupancy. progestin stimulation results in remodeling of these nucleosomes with displacement of histones h1 and h2a/ h2b dimers. our results strongly suggest that nucleosomes play crucial role in pr binding and hormonal gene regulation.

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Four enzymes cooperate to displace histone H1 during the first minute of hormonal gene activation

Cited by 102 publications

References 87 publications

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

More help than hindrance

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