Nucleosome-Driven Transcription Factor Binding and Gene Regulation

Ballaré, Cecilia; Castellano, Giancarlo; Gaveglia, Laura; Althammer, Sonja; González-Vallinas, Juan; Eyras, Eduardo; Dily, François Le; Zaurín, Roser; Soronellas, Daniel; Vicent, Guillermo P.; Beato, Miguel

doi:10.1016/j.molcel.2012.10.019

Cited by 132 publications

(192 citation statements)

References 56 publications

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“…Whole genome expression microarrays with cells stimulated for different times with Pg reveals around 4,000 hormone target genes, half of them upregulated and the other half downregulated. 2 The nature of the regulated genes is concordant with previous reports demonstrating a proliferative burst induced by progesterone in breast cancer cells. 13 Comparison of gene expression results with PR occupancy in response to hormone shows a significant enrichment of PRbs around Pg upregulated genes, which correlates with the magnitude of hormone response.…”

Section: Pr Binding Sites Are Marked By High Nucleosomes Occupancysupporting

confidence: 89%

“…Indeed, the PRbs show an enrichment of binding sites for members of several TF families, but none of them was significant enough to explain the large discrepancy between potential PRbs and actually bound sites. 2 Previous reports have shown that receptors for other steroid hormone bind preferentially to sites within regions of "open" chromatin, detected as DNaseI hypersensitive sites (DHS), 14 which are usually represented as depleted of nucleosome. We used DNaseI-sequencing (DNaseI-Seq) to determine genome wide the location of DHS in T47D-MTVL cells before and after hormone treatment.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Pr Binding Sites Are Marked By High Nucleosomes Occupancysupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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More help than hindrance

Ballaré

Zaurín

Vicent

et al. 2013

Nucleus

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“…Although most transcription factors cannot access nucleosomal DNA by themselves, pioneer transcription factors (e.g., FoxA) can bind to nucleosomal DNA and recruit other factors to bind (Cirillo et al 2002). Along these lines, the transcription factors p53 and PU.1 and the progesterone receptor, which apparently operates with FoxA1 (Clarke and Graham 2012), preferentially target their binding motifs amid sequences with high intrinsic nucleosome occupancy rather than high-affinity motifs with low intrinsic nucleosome occupancy (Lidor Nili et al 2010;Ballare et al 2013;Barozzi et al 2014). Thus, contrary to the dogma that nucleosomes would be inherently repressive to gene activity and must be removed for factor binding, pioneer transcription factors positively use the feature of high nucleosome occupancy at enhancers as their functional binding target ( Fig.…”

Section: Nucleosomes At Enhancers: a Collaborator For Pioneer Factorsmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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“…Indeed, the elegant demonstration of progesterone receptor binding to nucleosome PRE, recently published (35), further challenges this view. Our results are consistent with a model where ERα, in the absence of estrogen stimulation, collaborates with other transcription factors to maintain the luminal epithelial enhancer landscape.…”

Section: Significancementioning

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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Nucleosome-Driven Transcription Factor Binding and Gene Regulation

Cited by 132 publications

References 56 publications

More help than hindrance

More help than hindrance

Pioneer transcription factors in cell reprogramming

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

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