In vivo contribution of Cyp24a1 promoter vitamin D response elements
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1150259 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30316834_1.fastq.gz | Fastqsanger.gz | |||
| SRR30316834_2.fastq.gz | Fastqsanger.gz | |||
| SRR30316835_1.fastq.gz | Fastqsanger.gz | |||
| SRR30316835_2.fastq.gz | Fastqsanger.gz | |||
| SRR30316836_1.fastq.gz | Fastqsanger.gz |
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Project description:CYP24A1 is a multifunctional, P450 mitochondrial enzyme that catabolizes the vitamin D hormone (calcitriol, 1,25(OH)2D3), its precursor (calcifediol, 25(OH)D3), and numerous vitamin D metabolites. In the kidney, Cyp24a1 is induced by 1,25(OH)2D3 and fibroblast growth factor 23 (FGF23) and potently suppressed by PTH to control the circulating levels of 1,25(OH)2D3. Cyp24a1 is controlled by a pair of promoter proximal (PRO) vitamin D response elements (VDREs) that are aided by distal, downstream (DS) enhancers. The downstream 1 region of Cyp24a1 (DS1) enhancer is kidney-specific and responsible for PTH and FGF23 actions, and the downstream 2 region of Cyp24a1 enhancer responds to 1,25(OH)2D3 in all tissues. Despite this knowledge, in vivo contributions of the PRO VDREs to basal expression, FGF23 activation, and PTH suppression of Cyp24a1 remain unknown. In this study, we selectively mutated the PRO VDREs in the mouse to address these questions. We found mutation of the VDREs leads to a dramatic loss of VDR occupancy, a reduction of 1,25(OH)D3-induced kidney Cyp24a1 expression, and near elimination of intestinal Cyp24a1 induction. FGF23 induction of Cyp24a1 was reduced but not eliminated and still showed a synergistic increase with 1,25(OH)2D3. PTH suppression of Cyp24a1 was unchanged, despite minor reductions in total for phosphorylated cAMP-response element binding protein occupancy. Finally, VDR recruitment was dramatically reduced across the DS enhancers in the Cyp24a1 locus. Taken together, our data suggest a cooperative relationship between the DS and PRO enhancers in the regulation of Cyp24a1 by 1,25(OH)2D3 and FGF23 and points to the DS1 region as a crucial basal switch for Cyp24a1 activity that further defines the interconnected genomic control in vitamin D catabolism.
2024-08-25 | GSE275331 | GEO
Project description:Vitamin D (VD) exerts diverse physiological and pathological effects primarily through the vitamin D receptor (VDR), a ligand-dependent transcription factor. However, the limited number of known VDR target genes does not fully explain the broad spectrum of VD actions. In this study, we performed a comprehensive genome-wide analysis to identify enhancer RNAs (eRNAs) involved in VD-dependent gene regulation. Using integrated ChIP-seq, RNA-seq, and NET-CAGE analyses in human HCT116 and HaCaT cells, we mapped VDR binding sites and identified VD-responsive transcripts. VDR binding was strongly dependent on vitaminD and predominantly localized to enhancer regions marked by H3K27ac, indicating association with active chromatin. Through stepwise filtering, we identified a limited number of high-confidence eRNA candidates associated with VDR-bound regulatory regions. Among these, eRNAs located at the CYP24A1 locus were robustly induced by VD and correlated with strong transcriptional activation of the gene. Functional analyses using BET inhibition and LNA-mediated knockdown demonstrated that these eRNAs contribute to VD-dependent transcription. Furthermore, CRISPR/dCas9-mediated induction of specific eRNAs enhanced CYP24A1 expression, supporting a direct regulatory role. In contrast, newly identified target genes such as DLX2 and SYT8 exhibited modest, cell type–dependent responses to VD. Our findings reveal that VDR-mediated gene regulation involves a limited but functionally significant set of eRNAs, particularly at super-enhancer regions, and highlight a unique epigenetic mechanism underlying VD action.
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Project description:Vitamin D is a central regulator of mineral homeostasis, but its cell-type-specific effects are poorly understood. Here, we tested the effects of acute calcitriol injection on gene expressions in mouse kidneys and intestine (jejunum) using single-cell RNA sequencing.
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Project description:Genome-wide identification of vitamin D receptor–regulated enhancer RNAs reveals epigenetic regulation of CYP24A1 transcription
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Project description:Building on prior evidence implicating lncBCAS1-4_1 in resisting vitamin D signaling across cancer types, this study characterizes its mechanism of action in lung malignancies. Though induced by 1α,25(OH)2D3 treatment apart from CYP24A1 regulation, lncBCAS1-4_1 knockdown potentiated the growth-inhibitory impact of 1α,25(OH)2D3 on lung cancer cells. Orthotopic xenograft models validated lncBCAS1-4_1’s oncogenic potential, which was suppressible by supplemental vitamin D, but upregulated lncBCAS1-4_1 following 1,25(OH)2D3 treatment was independent of CYP24A1. Intriguingly, the knockdown of lncBCAS1-4_1 augmented the anti-proliferative and migrative effect of 1α,25(OH)2D3 on lung cancer cell in vitro. Using gain- and loss-of-function cell model, we demonstrated that lncBCAS1-4_1 functions as a negative feedback regulator that significantly blunts the therapeutic response to 1α,25(OH)₂D₃. While in vivo xenograft models showed that lncBCAS1-4_1 modulation alone had subtle effects on tumor initiation, its overexpression critically compromised the tumor-suppressive efficacy of 1α,25(OH)2D3 treatment. We uncover dual oncogenic mechanisms whereby lncBCAS1-4_1 not only accelerates EMT progression through its physical association with vimentin, but also transcriptionally upregulates key glycolytic regulators (HK2, LDHA, phosphorylated LDHA, and TKT). By simultaneously reprogramming cell plasticity and metabolic adaptability, lncBCAS1-4_1 emerges as a pivotal factor restricting the clinical utility of vitamin D monotherapy in lung cancer.
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Project description:Enhancer Cis Elements Instruct Promoter-Enhancer Interaction, Promoter-Enhancer Insulation and Compartmental Segregation
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Project description:Introduction: Biologically active vitamin D (1,25-dihydroxyvitamin D or 1,25D) has emerged as a key regulator of human innate immunity. 1,25D signaling in macrophages strongly induces the expression of neutrophil chemoattractants, such as IL-8/CXCL8. Meta-analysis of vitamin D-regulated expression profiles has suggested that 1,25D may regulate granule formation in granulocytic cells. Here, we have examined the effects of 1,25D signaling on human neutrophil gene expression, alone and in combination with the inflammatory signal lipopolysaccharide (LPS). These studies are of interest because, whereas 1,25D signaling boosts innate immunity, it is anti-inflammatory. Methods and results: We determined the effects of 1,25D alone and in combination with LPS on gene expression of primary human neutrophils by RNAseq. LPS did not affect or slightly enhanced the expression of several well-characterized 1,25D-target genes, but strongly suppressed that encoding the 1,25D catabolic enzyme CYP24A1. Chromatin immunoprecipitation (ChIP) assays revealed that 1,25D- dependent vitamin D receptor (VDR) binding to the major CYP24A1 enhancer was eliminated in neutrophils treated with LPS, whereas binding to other 1,25D-target genes was unaffected. Notably, LPS induced binding of transcriptional repressors MAFF and BACH1 to the major CYP24A1 enhancer region. In other studies, pathway analyses revealed that 1,25D suppressed LPS-induced genes encoding inflammatory proteins. In addition, RNAseq and confirmatory RT/qPCR studies revealed that 1,25D, both on its own and in combination with LPS, increased mRNA expression of genes encoding antimicrobial components of secretory granules, including that encoding cathelicidin antimicrobial peptide (CAMP). Consistently, exposure of neutrophils to 1,25D enhanced bacterial killing, as revealed by a 20-25% reduction in E. coli colonies incubated with 1,25D-treated neutrophil conditioned media. The increased bacterial killing by 1,25D is mediated by 1,25D- induced secretion of cathelicidin, as an antibody against LL-37, the active form of cathelicidin, blocked antimicrobial activity. Discussion: Collectively, the data suggest that LPS prolongs vitamin D signaling by suppressing expression of the 1,25D catabolic enzyme CYP24A1. 1,25D signaling in the presence of LPS attenuates the expression of several genes associated with LPS inflammatory responses, whereas 1,25D in the absence or presence of LPS enhances the release of antibacterial proteins secreted by neutrophils in response to infection.
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Project description:Enhancers harbor instructions encoded for the interactions between cis-elements and transcription factors to orchestrate lineage specific gene programs. Here we developed a modified method for chromosome conformation capture (3C), named MID Hi-C, to reveal how in mouse embryonic stem cells differential cooperation of enhancers and the chromatin remodeler BAF, as instructed by the underlying transcription factor motifs, modulate enhancer-promoter communication. We show that BAF-dependent enhancers permit genomic interactions beyond enhancer boundaries. BAF-dependent enhancers do not dictate genomic interactions within enhancer-promoter loop domains but rather act to instruct remote enhancer-promoter communication. In contrast, BAF-independent enhancers interact with promoter regions within tightly insulated enhancer-promoter loop domains that are marked by promoter and enhancer boundary elements. In addition, enhancer activeness modulated by BAF enforces compartment segregation. Based on these observations, we propose that enhancer cis elements instruct with great precision BAF-induced enhancer-promoter communication and compartmental segregation.
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Project description:Antimicrobial proteins form an essential chemical barrier that protects the intestinal epithelium from microbial invasion. REG3 family antimicrobial lectins are prominently induced by the microbiota, but how nutritional cues intersect with microbial signals to regulate their expression is poorly understood. Vitamin A plays a central role in mucosal adaptive immunity, but its contribution to epithelial innate immunity is unclear. Here, we show that dietary vitamin A promotes expression of REG3 antimicrobial lectins, including REG3G, in intestinal epithelial cells from both mice and humans. Vitamin A–dependent induction of REG3G expression is driven by retinoic acid and requires signaling through retinoic acid receptors (RARs). Mechanistically, RARs directly bind the Reg3g promoter adjacent to a binding site for STAT3, the transcription factor that transduces microbial signals, thereby integrating nutritional and microbial inputs at the level of REG3G transcription. Extending these findings, we demonstrate that vitamin A–retinoic acid signaling similarly promotes expression of α-defensin antimicrobial proteins. Together, these results define a transcriptional mechanism by which vitamin A enhances epithelial antimicrobial defenses to strengthen mucosal innate immunity.
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