Abstract
BackgroundThe impact of signal-dependent transcription factors, such as glucocorticoid receptor and nuclear factor kappa-b, on the three-dimensional organization of chromatin remains a topic of discussion. The possible scenarios range from remodeling of higher order chromatin architecture by activated transcription factors to recruitment of activated transcription factors to pre-established long-range interactions.ResultsUsing circular chromosome conformation capture coupled with next generation sequencing and high-resolution chromatin interaction analysis by paired-end tag sequencing of P300, we observed agonist-induced changes in long-range chromatin interactions, and uncovered interconnected enhancer–enhancer hubs spanning up to one megabase. The vast majority of activated glucocorticoid receptor and nuclear factor kappa-b appeared to join pre-existing P300 enhancer hubs without affecting the chromatin conformation. In contrast, binding of the activated transcription factors to loci with their consensus response elements led to the increased formation of an active epigenetic state of enhancers and a significant increase in long-range interactions within pre-existing enhancer networks. De novo enhancers or ligand-responsive enhancer hubs preferentially interacted with ligand-induced genes.ConclusionsWe demonstrate that, at a subset of genomic loci, ligand-mediated induction leads to active enhancer formation and an increase in long-range interactions, facilitating efficient regulation of target genes. Therefore, our data suggest an active role of signal-dependent transcription factors in chromatin and long-range interaction remodeling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0832-9) contains supplementary material, which is available to authorized users.
Highlights
The impact of signal-dependent transcription factors, such as glucocorticoid receptor and nuclear factor kappa-b, on the three-dimensional organization of chromatin remains a topic of discussion
P300 is recruited to latent distal binding sites by ligand activated Glucocorticoid receptor (GR) and/or nuclear factor kappa-b (NFκB) To gain insight into the impact of GR activation on the chromatin state and three-dimensional (3D) organization, we first performed chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) for GR, P300, epigenetic marks (H3K27ac, H3K4me3, and H3K4me1) and DNase I accessibility analysis
Ligand-induced P300 distal binding site (DBS) were highly enriched for glucocorticoid response elements (GREs), whereas AP1 was the most prevalent motif detected at pre-existing P300 sites (Fig. 1d)
Summary
The impact of signal-dependent transcription factors, such as glucocorticoid receptor and nuclear factor kappa-b, on the three-dimensional organization of chromatin remains a topic of discussion. Mechanisms of transcriptional response mediated by signal-dependent transcription factors (inducible TFs) are not well understood at the level of chromatin topology. Recent genome-wide studies have revealed that the majority of TF binding sites (up to 90 %) are distal to promoters and located in intragenic and intergenic regions [1,2,3,4,5,6,7,8,9] These studies collectively revealed cell-typespecific constellations of distal regulatory regions that change during differentiation and development in a Kuznetsova et al Genome Biology (2015) 16:264. Discrepancies between studies on inducible TF-mediated long-range chromatin contacts may be due to differences in resolution and methodology or to the use of asynchronous cells
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