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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells

ABSTRACT: Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells

PROVIDER: PRJNA549085 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10202900.fastq.gz	Fastqsanger.gz
	SRR10202901.fastq.gz	Fastqsanger.gz
	SRR10202902.fastq.gz	Fastqsanger.gz
	SRR10202903.fastq.gz	Fastqsanger.gz
	SRR10202904.fastq.gz	Fastqsanger.gz

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [4C-seq]

Project description:The CFTR gene lies within an invariant topologically associated domain (TAD) demarcated by CTCF and cohesin, but shows cell-type specific control mechanisms utilizing different cis-regulatory elements (CRE) within the TAD. Within the respiratory epithelium, more than one cell type expresses CFTR and the molecular mechanism controlling its transcription are likely divergent between them. Here we determine how two extragenic CREs that are prominent in secretory epithelial cells in the lung, regulate expression of the gene. We showed earlier that these CREs, located at -44kb and -35 kb upstream of the promoter, have strong cell-type-selective enhancer function. They are also responsive to inflammatory mediators and to oxidative stress, consistent with a key role in CF lung disease. Here we use CRISPR/Cas9 technology to remove these CREs from the endogenous locus in human bronchial epithelial cells. Loss of either site extinguished CFTR expression and abolished long-range interactions between these sites and the gene promoter. The deletions also greatly reduced promoter interactions with the 5’ TAD boundary. We show substantial recruitment of RNAPII to the -35kb element and identify CEBPβ as a key activating transcription factor for airway expression of CFTR, likely through occupancy at both the CRE and the gene promoter.

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [ChIP-seq]

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [Omni-ATAC-seq]

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [4C-seq]

Project description:Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [4C-seq]

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [ChIP-seq]

Project description:Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [ChIP-seq]

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [Omni-ATAC-seq]

Project description:Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [Omni-ATAC-seq]

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Differential contribution of cis-regulatory elements to higher order chromatin structure and expression of the CFTR locus

Project description:Higher order chromatin structure establishes domains that organize the genome and coordinate gene expression. However, the molecular mechanisms controlling transcription of individual loci within a topological domain (TAD) are not fully understood. The cystic fibrosis transmembrane conductance regulator (CFTR) gene provides a paradigm for investigating these mechanisms. CFTR occupies a TAD bordered by CTCF/cohesin binding sites within which are cell-type-selective cis-regulatory elements for the locus. We showed previously that intronic and extragenic enhancers, when occupied by specific transcription factors, are recruited to the CFTR promoter by a looping mechanism to drive gene expression. Here we use a combination of CRISPR/Cas9 editing of cis-regulatory elements and siRNA-mediated depletion of architectural proteins to determine the relative contribution of structural elements and enhancers to the higher order structure and expression of the CFTR locus. We found the boundaries of the CFTR TAD are conserved among diverse cell types and are dependent on CTCF and cohesin complex. Removal of an upstream CTCF-binding insulator alters the interaction profile, but has little effect on CFTR expression. Within the TAD, intronic enhancers recruit cell-type selective transcription factors and deletion of a pivotal enhancer element dramatically decreases CFTR expression, but has minor effect on its 3D structure. Examination of open chromatin region in Caco2 (colorectal adenocarcinoma cells), HBE (primary human bronchial epithelial cells), and primary adult human epididymis cells

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells.

Project description:The CFTR gene lies within an invariant topologically associated domain (TAD) demarcated by CTCF and cohesin, but shows cell-type specific control mechanisms utilizing different cis-regulatory elements (CRE) within the TAD. Within the respiratory epithelium, more than one cell type expresses CFTR and the molecular mechanisms controlling its transcription are likely divergent between them. Here, we determine how two extragenic CREs that are prominent in epithelial cells in the lung, regulate expression of the gene. We showed earlier that these CREs, located at -44 and -35 kb upstream of the promoter, have strong cell-type-selective enhancer function. They are also responsive to inflammatory mediators and to oxidative stress, consistent with a key role in CF lung disease. Here, we use CRISPR/Cas9 technology to remove these CREs from the endogenous locus in human bronchial epithelial cells. Loss of either site extinguished CFTR expression and abolished long-range interactions between these sites and the gene promoter, suggesting non-redundant enhancers. The deletions also greatly reduced promoter interactions with the 5' TAD boundary. We show substantial recruitment of RNAPII to the -35 kb element and identify CEBPβ as a key activator of airway expression of CFTR, likely through occupancy at this CRE and the gene promoter.

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Differential contribution of cis-regulatory elements to higher order chromatin structure and expression of the CFTR locus

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Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-22 | GSE132808 | GEO