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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165717 | GEO | 2021/11/17

REPOSITORIES: GEO

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BACH1, the master regulator of oxidative stress, modulates CFTR gene expression [RNA-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 | GSE165718 | GEO

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

2021-11-17 | GSE165716 | GEO

BACH1, the master regulator of oxidative stress, modulates CFTR gene expression

Project description:BACH1, the master regulator of oxidative stress, modulates CFTR gene expression

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

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

Project description:BACH1, the master regulator of oxidative stress, modulates CFTR gene expression [ChIP-seq]

| PRJNA695529 | ENA

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

Project description:BACH1, the master regulator of oxidative stress, modulates CFTR gene expression [RNA-seq]

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Expression data from wild type and Bach1 knock out ventral mid brains of two month old mice.

Project description:Bach1 is a known repressor of NRF2 transcription factor which governs oxidative stress during pathophysiology of Parkinson's disease. NRF2 activation in ventral midbrain is associated with protection against oxidative stress induced apoptosis of DA neurons. In this study we hve evaluated the effect of loss of Bach1 fucntion in ventral mid brains.

2021-12-29 | GSE164412 | GEO

BACH1 is a central regulator of glutathione metabolism, cellular necrosis and host resistance in Mycobacterium tuberculosis infection

Project description:Background. An exacerbated oxidative stress response can regulate cellular necrosis by triggering lipid peroxidation in an iron-dependent manner and this form of necrotic death has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. We found that BACH1 expression is associated with and predicts active pulmonary tuberculosis in humans. In response to Mtb infection in vitro and in vivo, ablation of Bach1 increased the levels of glutathione as well as enhanced the expression of Gpx4, an enzyme that regulates lipid peroxidation. Consistent with these observations, Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation accompanied by enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with suppression of ferroptosis. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that exhibits the necrotic lung pathology similar to that seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 and its regulation of the oxidative stress response as an important modulator of cellular and tissue necrosis as well as host resistance in Mtb infection.

2023-09-07 | GSE236853 | GEO

Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells [Omni-ATAC-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 | GSE132806 | GEO

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

2020-04-22 | GSE138166 | GEO

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