Chromatin Landscape Dictates HSF Binding to Target DNA Elements

Guertin, Michael J.; Lis, John T.

doi:10.1371/journal.pgen.1001114

Cited by 199 publications

(238 citation statements)

References 93 publications

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“…Of these, only a small minoritybetween 5,000 and 10,000 sites-are actually occupied by PPARγ in adipocytes (46,47,49). In principle, the binding at specific sites in vivo might depend on the following: (i) latent properties of the motif instance, not captured by the consensus sequence (30); (ii) cooperative binding in the immediate vicinity by other TFs expressed in the cell type (either directly through proteinprotein interactions or indirectly through cooperative competition with nucleosomes) (50); and (iii) differences in the accessibility of the sites due to the chromatin landscape (36,51,52).…”

Section: Resultsmentioning

confidence: 99%

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

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

163

142

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Enhancers regulate gene expression through the binding of sequence-specific transcription factors (TFs) to cognate motifs. Various features influence TF binding and enhancer function-including the chromatin state of the genomic locus, the affinities of the binding site, the activity of the bound TFs, and interactions among TFs. However, the precise nature and relative contributions of these features remain unclear. Here, we used massively parallel reporter assays (MPRAs) involving 32,115 natural and synthetic enhancers, together with high-throughput in vivo binding assays, to systematically dissect the contribution of each of these features to the binding and activity of genomic regulatory elements that contain motifs for PPARγ, a TF that serves as a key regulator of adipogenesis. We show that distinct sets of features govern PPARγ binding vs. enhancer activity. PPARγ binding is largely governed by the affinity of the specific motif site and higher-order features of the larger genomic locus, such as chromatin accessibility. In contrast, the enhancer activity of PPARγ binding sites depends on varying contributions from dozens of TFs in the immediate vicinity, including interactions between combinations of these TFs. Different pairs of motifs follow different interaction rules, including subadditive, additive, and superadditive interactions among specific classes of TFs, with both spatially constrained and flexible grammars. Our results provide a paradigm for the systematic characterization of the genomic features underlying regulatory elements, applicable to the design of synthetic regulatory elements or the interpretation of human genetic variation.gene regulation | transcription factor binding | systems biology

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Section: Resultsmentioning

confidence: 99%

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

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

163

142

View full text Add to dashboard Cite

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“…Recent work compared chromatin accessibility before and after induction of the Drosophila heat shock transcription factor (HSTF) (Guertin and Lis 2010) and the mammalian glucocorticoid receptor (GR) (John et al 2011); these studies concluded that the chromatin was already accessible prior to induction. Our results go beyond these studies by showing that positioned nucleosomes constitute the chromatin structure around the binding regions of most TFs.…”

Section: Discussionmentioning

confidence: 99%

“…It was discovered early on that some loosely packaged regions of chromatin were hypersensitive to cleavage by DNase I, and these regions might harbor regulatory DNA (Weintraub and Groudine 1976). The advent of high-throughput genomic techniques allowed systematic mapping of nucleosomes, and more recent studies showed that most genomic DNA is nucleosomal and that functional TF binding sites tend to be located in nucleosomedepleted regions (Guertin and Lis 2010;John et al 2011;Li et al 2011). Nonetheless, some TFs are capable of remodeling nucleosomes in the absence of additional factors, and other TFs can recruit nucleosome remodelers to reposition or evict nucleosomes and expose TF binding sites (Berger 2007;Clapier and Cairns 2009).…”

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confidence: 99%

Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors

et al. 2012

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Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) has become the dominant technique for mapping transcription factor (TF) binding regions genome-wide. We performed an integrative analysis centered around 457 ChIP-seq data sets on 119 human TFs generated by the ENCODE Consortium. We identified highly enriched sequence motifs in most data sets, revealing new motifs and validating known ones. The motif sites (TF binding sites) are highly conserved evolutionarily and show distinct footprints upon DNase I digestion. We frequently detected secondary motifs in addition to the canonical motifs of the TFs, indicating tethered binding and cobinding between multiple TFs. We observed significant position and orientation preferences between many cobinding TFs. Genes specifically expressed in a cell line are often associated with a greater occurrence of nearby TF binding in that cell line. We observed cell-linespecific secondary motifs that mediate the binding of the histone deacetylase HDAC2 and the enhancer-binding protein EP300. TF binding sites are located in GC-rich, nucleosome-depleted, and DNase I sensitive regions, flanked by wellpositioned nucleosomes, and many of these features show cell type specificity. The GC-richness may be beneficial for regulating TF binding because, when unoccupied by a TF, these regions are occupied by nucleosomes in vivo. We present the results of our analysis in a TF-centric web repository Factorbook (http://factorbook.org) and will continually update this repository as more ENCODE data are generated.

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“…Whereas the nucleotide content of the TFBS is known to be a major determinant of TF binding, genome-wide TF binding patterns cannot be explained solely by this effect (Liu et al 2006;Guertin and Lis 2010;Zhou and O'Shea 2011;Gordan et al 2013;White et al 2013). In fact, for the same TFBS, occurrences in different genomic locations were found to display differential binding (Liu et al 2006;Guertin and Lis 2010;Gordan et al 2013;White et al 2013).…”

Section: Quantitative Measurements Of Tf Binding To Thousands Of Desimentioning

confidence: 99%

Unraveling determinants of transcription factor binding outside the core binding site

et al. 2015

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Binding of transcription factors (TFs) to regulatory sequences is a pivotal step in the control of gene expression. Despite many advances in the characterization of sequence motifs recognized by TFs, our ability to quantitatively predict TF binding to different regulatory sequences is still limited. Here, we present a novel experimental assay termed BunDLE-seq that provides quantitative measurements of TF binding to thousands of fully designed sequences of 200 bp in length within a single experiment. Applying this binding assay to two yeast TFs, we demonstrate that sequences outside the core TF binding site profoundly affect TF binding. We show that TF-specific models based on the sequence or DNA shape of the regions flanking the core binding site are highly predictive of the measured differential TF binding. We further characterize the dependence of TF binding, accounting for measurements of single and co-occurring binding events, on the number and location of binding sites and on the TF concentration. Finally, by coupling our in vitro TF binding measurements, and another application of our method probing nucleosome formation, to in vivo expression measurements carried out with the same template sequences serving as promoters, we offer insights into mechanisms that may determine the different expression outcomes observed. Our assay thus paves the way to a more comprehensive understanding of TF binding to regulatory sequences and allows the characterization of TF binding determinants within and outside of core binding sites.

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Chromatin Landscape Dictates HSF Binding to Target DNA Elements

Cited by 199 publications

References 93 publications

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors

Unraveling determinants of transcription factor binding outside the core binding site

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