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Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109590 | GEO | 2018/05/08

REPOSITORIES: GEO

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Different chromatin and DNA sequence characteristics define glucocorticoid receptor binding sites that are blocked or not blocked by coregulator Hic-5.

Project description:The glucocorticoid receptor (GR) regulates genes in many physiological pathways by binding to enhancer and silencer elements of target genes, where it recruits coregulator proteins that remodel chromatin and regulate the assembly of transcription complexes. The coregulator Hydrogen peroxide-inducible clone 5 (Hic-5) is necessary for glucocorticoid (GC) regulation of one group of GR target genes, is irrelevant for a second group, and inhibits GR binding to a third gene set, thereby blocking their regulation by GC. Gene-specific characteristics that distinguish GR binding regions (GBR) at Hic-5 blocked genes from GBR at other GC-regulated genes are unknown. Here we show genome-wide that blocked GBR generally require CHD9 and BRM for GR occupancy in contrast to GBR that are not blocked by Hic-5. Hic-5 blocked GBR are enriched near Hic-5 blocked GR target genes but not near GR target genes that are not blocked by Hic-5. Furthermore blocked GBR are in a closed conformation prior to Hic-5 depletion, and require Hic-5 depletion and glucocorticoid treatment to create an open conformation necessary for GR occupancy. A transcription factor binding motif characteristic of the ETS family was enriched near blocked GBR and blocked genes but not near non-blocked GBR or non-blocked GR target genes. Thus, we identify specific differences in chromatin conformation, chromatin remodeler requirements, and local DNA sequence motifs that contribute to gene-specific actions of transcription factors and coregulators. These findings shed light on mechanisms that contribute to binding site selection by transcription factors, which vary in a cell type-specific manner.

| S-EPMC5940187 | biostudies-literature

Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5 [ATAC-seq]

Project description:The glucocorticoid-activated glucocorticoid receptor (GR) regulates cellular stress pathways by binding to genomic regulatory elements of target genes and recruiting coregulator proteins to remodel chromatin and regulate transcription complex assembly. The coregulator Hydrogen peroxide-inducible clone 5 (Hic-5) is required for glucocorticoid regulation of some genes, but not others, and blocks regulation of a third gene set. Hic-5 inhibits GR binding to blocked genes but not other glucocorticoid-regulated genes. Site-specific blocking of GR binding is due to gene-specific requirements for ATP-dependent chromatin remodeling enzymes. We investigate the effects of Hic-5 and dexamethasone on chromatin accessibility at GR binding sites near Hic-5 blocked genes and non-blocked genes.

2018-05-08 | GSE109589 | GEO

Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5 [ChIP-seq]

Project description:The glucocorticoid-activated glucocorticoid receptor (GR) regulates cellular stress pathways by binding to genomic regulatory elements of target genes and recruiting coregulator proteins to remodel chromatin and regulate transcription complex assembly. The coregulator Hydrogen peroxide-inducible clone 5 (Hic-5) is required for glucocorticoid regulation of some genes, but not others, and blocks regulation of a third gene set. Hic-5 inhibits GR binding to blocked genes but not other glucocorticoid-regulated genes. Site-specific blocking of GR binding is due to gene-specific requirements for ATP-dependent chromatin remodeling enzymes. We investigate whether ATPases CHD9 and BRM were required for GR occupancy at GR binding sites near Hic-5 blocked genes.

2018-05-08 | GSE109383 | GEO

Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5

Project description:Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5

| PRJNA431430 | ENA

Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5 [ChIP-seq]

Project description:Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5 [ChIP-seq]

| PRJNA430719 | ENA

Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5 [ATAC-seq]

Project description:Different Chromatin and DNA Sequence Characteristics Define Glucocorticoid Receptor Binding Sites that are Blocked or Not Blocked by Coregulator Hic-5 [ATAC-seq]

| PRJNA431440 | ENA

Glucocorticoid receptor binding to chromatin is selectively controlled by the coregulator Hic-5 and chromatin remodeling enzymes.

Project description:The steroid hormone-activated glucocorticoid receptor (GR) regulates cellular stress pathways by binding to genomic regulatory elements of target genes and recruiting coregulator proteins to remodel chromatin and regulate transcription complex assembly. The coregulator hydrogen peroxide-inducible clone 5 (Hic-5) is required for glucocorticoid (GC) regulation of some genes but not others and blocks the regulation of a third gene set by inhibiting GR binding. How Hic-5 exerts these gene-specific effects and specifically how it blocks GR binding to some genes but not others is unclear. Here we show that site-specific blocking of GR binding is due to gene-specific requirements for ATP-dependent chromatin remodeling enzymes. By depletion of 11 different chromatin remodelers, we found that ATPases chromodomain helicase DNA-binding protein 9 (CHD9) and Brahma homologue (BRM, a product of the SMARCA2 gene) are required for GC-regulated expression of the blocked genes but not for other GC-regulated genes. Furthermore, CHD9 and BRM were required for GR occupancy and chromatin remodeling at GR-binding regions associated with blocked genes but not at GR-binding regions associated with other GC-regulated genes. Hic-5 selectively inhibits GR interaction with CHD9 and BRM, thereby blocking chromatin remodeling and robust GR binding at GR-binding sites associated with blocked genes. Thus, Hic-5 regulates GR binding site selection by a novel mechanism, exploiting gene-specific requirements for chromatin remodeling enzymes to selectively influence DNA occupancy and gene regulation by a transcription factor.

| S-EPMC5454112 | biostudies-literature

Selective enhancement and repression of glucocorticoid receptor signaling by coregulator Hic-5

Project description:The glucocorticoid receptor (GR) recruits many coregulators via the well characterized AF2 interaction surface in the GR ligand binding domain, but LIM domain coregulator Hic-5 binds to the relatively uncharacterized tau2 activation domain in the hinge region of GR. Requirement of Hic-5 for glucocorticoid-regulated gene expression in U2OS osteosarcoma cells was defined by Hic-5 depletion and global gene expression analysis. Hic-5 depletion had selective and dramatic effects, positive and negative, on both activation and repression of GR target genes. For some hormone-induced genes, Hic-5 facilitated recruitment of the Mediator complex and RNA polymerase II. In contrast, many genes were not regulated by hormone until Hic-5 was depleted. On these genes Hic-5 acted at a very early step of the regulatory process, preventing efficient GR binding on enhancers, chromatin remodeling, and thus preventing glucocorticoid-driven transcriptional regulation. Overall, Hic-5 has selective and diverse roles on GR target genes, functioning as coactivator on some genes and corepressor on others, and either facilitating or opposing the glucocorticoid-driven actions of GR. Hic-5 exhibits multiple mechanisms of action, either regulating GR binding to DNA and chromatin remodeling, or facilitating later steps in transcription complex assembly. We investigate the relationship between GR and Hic5 and identify classes of genes that respond differently when cells are induced with hormone and when Hic5 is knocked down We knock down Hic-5 (TGFB1I1) in U2OS cells using siRNA (siHic5_2) along with nonspecific siRNA (shNS) and assay gene expression changes at 4 different time points of hormone treatment. We also include non-infected control (NI) as a second control at each time point.

2014-03-21 | E-GEOD-46448 | biostudies-arrayexpress

Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner.

Project description:Ligand activation and DNA-binding dictate the outcome of glucocorticoid receptor (GR)-mediated transcriptional regulation by inducing diverse receptor conformations that interact differentially with coregulators. GR recruits many coregulators via the well-characterized AF2 interaction surface in the GR ligand-binding domain, but Lin11, Isl-1, Mec-3 (LIM) domain coregulator Hic-5 (TGFB1I1) binds to the relatively uncharacterized tau2 activation domain in the hinge region of GR. Requirement of hydrogen peroxide-inducible clone-5 (Hic-5) for glucocorticoid-regulated gene expression was defined by Hic-5 depletion and global gene-expression analysis. Hic-5 depletion selectively affected both activation and repression of GR target genes, and Hic-5 served as an on/off switch for glucocorticoid regulation of many genes. For some hormone-induced genes, Hic-5 facilitated recruitment of Mediator complex. In contrast, many genes were not regulated by glucocorticoid until Hic-5 was depleted. On these genes Hic-5 prevented GR occupancy and chromatin remodeling and thereby inhibited their hormone-dependent regulation. Transcription factor binding to genomic sites is highly variable among different cell types; Hic-5 represents an alternative mechanism for regulating transcription factor-binding site selection that could apply both within a given cell type and among different cell types. Thus, Hic-5 is a versatile coregulator that acts by multiple gene-specific mechanisms that influence genomic occupancy of GR as well transcription complex assembly.

| S-EPMC3964041 | biostudies-literature

Selective enhancement and repression of glucocorticoid receptor signaling by coregulator Hic-5

2014-03-21 | GSE46448 | GEO