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

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

PROVIDER: PRJNA574955 | 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.

2020-04-22 | GSE138166 | GEO

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

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

| PRJNA549085 | ENA

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

2020-04-22 | GSE132807 | GEO

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

2020-04-22 | GSE132806 | GEO

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]

| PRJNA549087 | ENA

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]

| PRJNA549086 | ENA

An ectopic enhancer restores CFTR expression through de novo chromatin looping [4C-seq]

Project description:Transcription of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is regulated by a set of ubiquitous and cell-type selective cis-regulatory elements (CREs). These elements include extragenic and intronic enhancers that bind cell-type specific transcription factors, as well as architectural protein bound structural elements. We previously reported that loss of the airway-selective -35kb enhancer in 16HBE14o- airway epithelial cells disrupts normal enhancer-promoter looping at the CFTR locus and nearly abolishes its expression. Here we expand on previous work, and explore the effect of relocation of the 500bp -35kb enhancer core to an ectopic site in intron 1 of CFTR on gene expression and chromatin dynamics. We find that although genomic relocation of this element is not able to fully restore CFTR expression to wild-type levels, the -35kb sequence is able establish a de novo enhancer signature at chromatin at the site of insertion. Additionally, the relocated -35kb enhancer is able to form chromatin contacts with known CFTR CREs. These studies reveal important direct chromatin effects, as well as limitations, of CFTR enhancers, and provide important considerations when targeting the CFTR locus for novel therapeutic gene editing.

2022-12-13 | GSE203559 | GEO

An ectopic enhancer restores CFTR expression through de novo chromatin looping [4C-seq]

Project description:An ectopic enhancer restores CFTR expression through de novo chromatin looping [4C-seq]

| PRJNA841376 | ENA

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.

| S-EPMC7144911 | biostudies-literature

BACH1, the master regulator of oxidative stress, modulates CFTR gene expression [4C-seq]

Project description:The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within a TAD in which multiple cis-regulatory elements (CREs) and transcription factors (TFs) regulate its cell-specific expression. The CREs are recruited to the gene promoter by a looping mechanism that depends upon both architectural proteins and specific TFs. An siRNA screen to identify TFs coordinating CFTR expression in airway epithelial cells suggested an activating role for BTB Domain and CNC Homolog 1 (BACH1). BACH1 is a ubiquitous master regulator of the cellular response to oxidative stress. Here we show that BACH1 may have a dual effect on CFTR expression by direct occupancy of CREs at physiological oxygen (~8%), while indirectly modulating expression under conditions of oxidative stress. Hence BACH1, can activate or repress the same gene, to fine tune expression in response to environmental cues such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also directly regulate CFTR gene expression by modulating locus architecture through occupancy at known enhancers and structural elements, and depletion of BACH1 alters the higher order chromatin structure.

2021-11-17 | GSE165716 | GEO

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