Chromatin accessibility pre-determines glucocorticoid receptor binding patterns

By S. John, P. Sabo, Robert E. Thurman, Myong-Hee Sung, S. Biddie, T. Johnson, G. Hager, John A. Stamatoyannopoulos. Nature Genetics, 2011

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Development, differentiation and response to environmental stimuli are characterized by sequential changes in cellular state initiated by the de novo binding of regulated transcriptional factors to their cognate genomic sites. The mechanism whereby a given regulatory factor selects a limited number of in vivo targets from a myriad of potential genomic binding sites is undetermined. Here we show that up to 95% of de novo genomic binding by the glucocorticoid receptor, a paradigmatic ligand-activated transcription factor, is targeted to preexisting foci of accessible chromatin. Factor binding invariably potentiates chromatin accessibility. Cell-selective glucocorticoid receptor occupancy patterns appear to be comprehensively predetermined by cell-specific differences in baseline chromatin accessibility patterns, with secondary contributions from local sequence features. The results define a framework for understanding regulatory factor–genome interactions and provide a molecular basis for the tissue selectivity of steroid pharmaceuticals and other agents that intersect the living genome.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/014f9303a7ccdb8f4d7a15ad3cd5bc771517766c

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Citations in the corpus

The Biology of the Glucocorticoid Receptor: New Signaling Mechanisms in Health and Disease (2013, background): “Global GR recruitment assays indicate that only a small fraction of GREs are actually occupied by the receptor, and the specific sites of GR binding vary in a tissue-specific manner due to differences in chromatin accessibility and exposure of the GRE (28).”
Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors (2012, background): “…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).”
Pioneer transcription factors: establishing competence for gene expression. (2011, background): “Although such target sequences may be a minority for GR at the genomic level (John et al. 2011), the sites where GR induces hypersensitivity are where other factors can subsequently enter the chromatin and therefore represent regions where GR serves as a pioneer factor (Voss et al.”
A Comparative Encyclopedia of DNA Elements in the Mouse Genome (2014, background): “Previous studies revealed limited changes of the chromatin states in lineage-restricted cells as they undergo large-scale changes in gene expression during maturation 51–53 .”
Analysis of computational footprinting methods for DNase sequencing experiments (2016, methodology): “GR (dexamethasone treatment) ChIP-seq raw sequences for m3134 cell type was obtained in the sequence read archive (SRA) under study number SRP004871 31 .”
An encyclopedia of mouse DNA elements (Mouse ENCODE) (2012, methodology): “…Additional file 1 span many highutility data types generated using stateoftheart approaches, including DNaseI hypersensitive sites by DNaseseq [19], DNaseI footprints by digital genomic footprinting [20], RNAseq [21], histone modifications by ChIPseq [22], transcrip tion factor and…”
Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription (2013, background): “…in which cell signaling induces nuclear entry and DNA binding of regulated transcription factors, such as steroid hormone receptors and NF-kB, the majority of binding events take place at genomic locations that exhibit pre-existing enhancer-like features (Barish et al., 2010; John et al., 2011).”
CG methylated microarrays identify a novel methylated sequence bound by the CEBPB|ATF4 heterodimer that is active in vivo (2013, background): “…in vivo binding of CEBPB to the unmethylated CEBP se- quences, even though they are bound more poorly on the array, is because the unmethylated occurrences are in more accessible Genome Research 993 www.genome.org regions of the genome (Biddie et al. 2011; John et al. 2011; Stadler et al. 2011).”