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Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements

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Item Type:Article
Title:Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements
Creators Name:Telorac, J., Prykhozhij, S.V., Schöne, S., Meierhofer, D., Sauer, S., Thomas-Chollier, M. and Meijsing, S.H.
Abstract:Out of the myriad of potential DNA binding sites of the glucocorticoid receptor (GR) found in the human genome, only a cell-type specific minority is actually bound, indicating that the presence of a recognition sequence alone is insufficient to specify where GR binds. Cooperative interactions with other transcription factors (TFs) are known to contribute to binding specificity. Here, we reasoned that sequence signals preventing GR recruitment to certain loci provide an alternative means to confer specificity. Motif analyses uncovered candidate Negative Regulatory Sequences (NRSs) that interfere with genomic GR binding. Subsequent functional analyses demonstrated that NRSs indeed prevent GR binding to nearby response elements. We show that NRS activity is conserved across species, found in most tissues and that they also interfere with the genomic binding of other TFs. Interestingly, the effects of NRSs appear not to be a simple consequence of changes in chromatin accessibility. Instead, we find that NRSs interact with proteins found at sub-nuclear structures called paraspeckles and that these proteins might mediate the repressive effects of NRSs. Together, our studies suggest that the joint influence of positive and negative sequence signals partition the genome into regions where GR can bind and those where it cannot.
Keywords:Base Sequence, Binding Sites, Chromatin, DNA-Binding Proteins, Genetic Promoter Regions, Glucocorticoid Receptors, Response Elements, Transcription Factors
Source:Nucleic Acids Research
Publisher:Oxford University Press
Page Range:6142-6156
Date:27 July 2016
Official Publication:https://doi.org/10.1093/nar/gkw203
PubMed:View item in PubMed

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