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2018 ; 46
(6
): 2868-2882
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gab.com Text
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Genomic dissection of enhancers uncovers principles of combinatorial regulation
and cell type-specific wiring of enhancer-promoter contacts
#MMPMID29385519
Thormann V
; Rothkegel MC
; Schöpflin R
; Glaser LV
; Djuric P
; Li N
; Chung HR
; Schwahn K
; Vingron M
; Meijsing SH
Nucleic Acids Res
2018[Apr]; 46
(6
): 2868-2882
PMID29385519
show ga
Genomic binding of transcription factors, like the glucocorticoid receptor (GR),
is linked to the regulation of genes. However, as we show here, GR binding is a
poor predictor of GR-dependent gene regulation even when taking the 3D
organization of the genome into account. To connect GR binding sites to the
regulation of genes in the endogenous genomic context, we turned to genome
editing. By deleting GR binding sites, individually or in combination, we
uncovered how cooperative interactions between binding sites contribute to the
regulation of genes. Specifically, for the GR target gene GILZ, we show that the
simultaneous presence of a cluster of GR binding sites is required for the
activity of an individual enhancer and that the GR-dependent regulation of GILZ
depends on multiple GR-bound enhancers. Further, by deleting GR binding sites
that are shared between different cell types, we show how cell type-specific
genome organization and enhancer-blocking can result in cell type-specific wiring
of promoter-enhancer contacts. This rewiring allows an individual GR binding site
shared between different cell types to direct the expression of distinct
transcripts and thereby contributes to the cell type-specific consequences of
glucocorticoid signaling.