BRG1 governs Glucocorticoid Receptor interactions with chromatin and pioneer factors across the genome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA447949 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6914680_1.fastq.gz | Fastqsanger.gz | |||
| SRR6914680_2.fastq.gz | Fastqsanger.gz | |||
| SRR6914690_1.fastq.gz | Fastqsanger.gz | |||
| SRR6914690_2.fastq.gz | Fastqsanger.gz | |||
| SRR6914700_1.fastq.gz | Fastqsanger.gz |
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Project description:The Glucocorticoid Receptor (GR) alters transcriptional activity in response to hormones by interacting with chromatin at GR binding sites (GBSs) throughout the genome. Our work in human breast cancer cells identifies three classes of GBSs with distinct epigenetic characteristics and reveals that BRG1 interacts with GBSs prior to hormone exposure. The GBSs pre-occupied by BRG1 are more accessible and transcriptionally active than other GBSs. BRG1 is required for a proper and robust transcriptional hormone response and knockdown of BRG1 blocks recruitment of the pioneer factors FOXA1 and GATA3 to GBSs. Finally, GR interaction with FOXA1 and GATA3 binding sites was restricted to sites pre-bound by BRG1. These findings demonstrate that BRG1 establishes specialized chromatin environments that define multiple classes of GBS. This in turn predicts that GR and other transcriptional activators function via multiple distinct chromatin-based mechanisms to modulate the transcriptional response.
2018-05-22 | GSE112491 | GEO
Project description:The Glucocorticoid Receptor (GR) alters transcriptional activity in response to hormones by interacting with chromatin at GR binding sites (GBSs) throughout the genome. Our work in human breast cancer cells identifies three classes of GBSs with distinct epigenetic characteristics and reveals that BRG1 interacts with GBSs prior to hormone exposure. The GBSs pre-occupied by BRG1 are more accessible and transcriptionally active than other GBSs. BRG1 is required for a proper and robust transcriptional hormone response and knockdown of BRG1 blocks recruitment of the pioneer factors FOXA1 and GATA3 to GBSs. Finally, GR interaction with FOXA1 and GATA3 binding sites was restricted to sites pre-bound by BRG1. These findings demonstrate that BRG1 establishes specialized chromatin environments that define multiple classes of GBS. This in turn predicts that GR and other transcriptional activators function via multiple distinct chromatin-based mechanisms to modulate the transcriptional response.
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Project description:The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the ATPase subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression, however aberrant remodeling and gene expression can result in cancer. The function and localization on chromatin of the SWI/SNF complex depends on the protein makeup of the complex. Here we report the protein-protein interactions of wild-type BRG1 or mutant BRG1 in which the HSA domain has been deleted (BRG1-HSA). We demonstrate the interaction of BRG1 with most SWI/SNF complex members and a failure of a number of these members to interact with BRG1-HSA. These results demonstrate that the HSA domain of BRG1 is a critical interaction platform for the correct formation of SWI/SNF remodeling complexes.
2023-02-15 | PXD029647 | Pride
Project description:The glucocorticoid receptor (GR) regulates transcription through binding to specific DNA motifs, particularly at enhancers. While the motif to which it binds is constant across cell types, GR has cell-type specific binding at genomic loci, resulting in expression of different genes. The presence of other bound transcription factors (TFs) is hypothesized to specify where GR binds. Here, we addressed the roles of other TFs in the glucocorticoid response by comparing changes in GR binding and nascent transcription at candidate cis-regulatory elements in two distinct cell types. We found that each cell type binds GR at thousands of non-overlapping loci, but only a small fraction of these sites also show changes in transcription. GR binding is associated with pioneer factor binding, whereas transcription is induced at sites bound by AP-1. These results support a model of transcriptional regulation in which multiple classes of TFs are required. The pioneer factors increase chromatin accessibility, facilitating the binding of GR and additional factors. AP-1 then poises a fraction of sites to be rapidly activated upon glucocorticoid-induced GR binding. GR also induces transcription at a specific set of enhancers. The coordinated activity of multiple TFs then results in cell-type specific changes in gene expression. We anticipate that many models of inducible gene expression also require multiple distinct TFs that act at multiple rate-limited steps of transcriptional regulation.
2021-06-01 | GSE168767 | GEO
Project description:Glucocorticoid hormone plays a major role in metabolism and many related diseases. The hormone-bound glucocorticoid receptor (GR) binds to a specific set of enhancers in different cell types, resulting in unique patterns of gene expression. GR-responsive enhancers have an accessible chromatin structure prior to hormone treatment (“pre-programmed”), whereas unresponsive enhancers specific to other cell types are inaccessible and inactive. Here we have addressed the role of chromatin structure in cell-specific GR-enhancer programming by precise mapping of nucleosome positions in mouse adenocarcinoma cells. We show that, before hormone treatment, some pre-programmed GR-enhancers are nucleosome-depleted, associated with the Brg1 chromatin remodeler and flanked by nucleosomes exchanging histones H2A.Z and H2A. However, most pre-programmed GR-enhancers are assembled into a nucleosome that exchanges H2A.Z and H2A, with little or no Brg1. After hormone treatment, nucleosomes at both types of pre-programmed GR-enhancer shift apart, coinciding with increased levels of Brg1, and continue to exchange H2A.Z and H2A. Hormone removal rapidly reverses these nucleosome shifts. In contrast, inactive GR-enhancers are nucleosomal, lack Brg1, do not exchange H2A.Z or H2A and do not respond to hormone. Thus, pre-programmed GR-enhancers are marked by a dynamic, mutable chromatin structure characterized by high levels of H2A.Z exchange. We propose that nucleosome-depleted GR-enhancers result from the binding of other transcription factors together with Brg1 to assist loading of GR after hormone treatment. At nucleosomal enhancers, GR binding may be directly facilitated by increased transient exposure of enhancer DNA associated with H2A.Z exchange.
2017-11-06 | GSE92505 | GEO
Project description:Pioneer transcription factors are able to recognise and bind their motif sequences in inaccessible or closed chromatin, and their ability to achieve this is required to establish new regulatory elements and transcriptional networks during development and cellular reprogramming. An essential feature of this pioneering activity is the transition from inaccessible chromatin to a nucleosome-depleted and accessible chromatin state typical of normal regulatory elements, and this is believed to facilitate further transcription factor binding events. However, the mechanisms by which many pioneer transcription factors achieve this remarkable feat remain elusive. Here we reveal that the pluripotency-associated pioneer factor OCT4 binds inaccessible chromatin to shape the chromatin accessibility, transcription factor co-binding and regulatory potential of thousands of distal regulatory elements in mouse embryonic stem cells, demonstrating that its pioneering activity is a feature of normal pluripotency, and not just reprogramming. The accessible chromatin formed at OCT4 binding sites relies on the chromatin remodelling factor BRG1, which is recruited to these sites by OCT4. The occupancy of BRG1 is then required to support OCT4/SOX2 co-binding and normal expression of the pluripotency-associated transcriptome, and this reliance on BRG1 reflects OCT4 binding dynamics during cellular reprograming and early mouse development. Together these observations reveal a distinct requirement for the chromatin remodelling factor BRG1 in shaping the pioneering activity of OCT4 and regulating the pluripotency network in embryonic stem cells.
2017-03-13 | GSE87821 | GEO
Project description:Pioneer transcription factors are able to recognise and bind their motif sequences in inaccessible or closed chromatin, and their ability to achieve this is required to establish new regulatory elements and transcriptional networks during development and cellular reprogramming. An essential feature of this pioneering activity is the transition from inaccessible chromatin to a nucleosome-depleted and accessible chromatin state typical of normal regulatory elements, and this is believed to facilitate further transcription factor binding events. However, the mechanisms by which many pioneer transcription factors achieve this remarkable feat remain elusive. Here we reveal that the pluripotency-associated pioneer factor OCT4 binds inaccessible chromatin to shape the chromatin accessibility, transcription factor co-binding and regulatory potential of thousands of distal regulatory elements in mouse embryonic stem cells, demonstrating that its pioneering activity is a feature of normal pluripotency, and not just reprogramming. The accessible chromatin formed at OCT4 binding sites relies on the chromatin remodelling factor BRG1, which is recruited to these sites by OCT4. The occupancy of BRG1 is then required to support OCT4/SOX2 co-binding and normal expression of the pluripotency-associated transcriptome, and this reliance on BRG1 reflects OCT4 binding dynamics during cellular reprograming and early mouse development. Together these observations reveal a distinct requirement for the chromatin remodelling factor BRG1 in shaping the pioneering activity of OCT4 and regulating the pluripotency network in embryonic stem cells.
2017-03-13 | GSE87820 | GEO
Project description:Pioneer transcription factors are able to recognise and bind their motif sequences in inaccessible or closed chromatin, and their ability to achieve this is required to establish new regulatory elements and transcriptional networks during development and cellular reprogramming. An essential feature of this pioneering activity is the transition from inaccessible chromatin to a nucleosome-depleted and accessible chromatin state typical of normal regulatory elements, and this is believed to facilitate further transcription factor binding events. However, the mechanisms by which many pioneer transcription factors achieve this remarkable feat remain elusive. Here we reveal that the pluripotency-associated pioneer factor OCT4 binds inaccessible chromatin to shape the chromatin accessibility, transcription factor co-binding and regulatory potential of thousands of distal regulatory elements in mouse embryonic stem cells, demonstrating that its pioneering activity is a feature of normal pluripotency, and not just reprogramming. The accessible chromatin formed at OCT4 binding sites relies on the chromatin remodelling factor BRG1, which is recruited to these sites by OCT4. The occupancy of BRG1 is then required to support OCT4/SOX2 co-binding and normal expression of the pluripotency-associated transcriptome, and this reliance on BRG1 reflects OCT4 binding dynamics during cellular reprograming and early mouse development. Together these observations reveal a distinct requirement for the chromatin remodelling factor BRG1 in shaping the pioneering activity of OCT4 and regulating the pluripotency network in embryonic stem cells.
2017-03-13 | GSE87819 | GEO
Project description:Glucocorticoid receptor collaborates with pioneer factors and AP-1 to execute genome-wide regulation
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Project description:We report that BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex, was required for the homeostatic maintenance of colonic epithelial cells (IECs) to prevent the inflammation and tumorigenesis. Consistent with the reduced BRG1 expression in IBD patients, adult mice with IEC ablation of BRG1 developed spontaneous colitis and exhibited increased susceptibility to mutagen-induced tumor growth. Conversely, BRG1 overexpression protected the mice from DSS-induced epithelial damage and subsequent oncogenesis. Mechanistically, BRG1 emerged as a key regulator that directly governs the transcription of Atg16l1, Ambra1, Atg7 and Wipi2, which are important for autophagosome biogenesis. Thus, defective autophagy in BRG1-deficient IECs resulted in excess reactive oxygen species (ROS), which led to the defects in cellular apoptosis and barrier integrity.
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