Vitamin D receptor and STAT6 interactome governs oesophageal epithelial barrier responses to IL-13 signalling.

OBJECTIVE: The contribution of vitamin D (VD) deficiency to the pathogenesis of allergic diseases remains elusive. We aimed to define the impact of VD on oesophageal allergic inflammation. DESIGN: We assessed the genomic distribution and function of VD receptor (VDR) and STAT6 using histology, molecular imaging, motif discovery and metagenomic analysis. We examined the role of VD supplementation in oesophageal epithelial cells, in a preclinical model of IL-13-induced oesophageal allergic inflammation and in human subjects with eosinophilic oesophagitis (EoE). RESULTS: VDR response elements were enriched in oesophageal epithelium, suggesting enhanced VDR binding to functional gene enhancer and promoter regions. Metagenomic analysis showed that VD supplementation reversed dysregulation of up to 70% of the transcriptome and epigenetic modifications (H3K27Ac) induced by IL-13 in VD-deficient cells, including genes encoding the transcription factors HIF1A and SMAD3, endopeptidases (SERPINB3) and epithelial-mesenchymal transition mediators (TGFBR1, TIAM1, SRC, ROBO1, CDH1). Molecular imaging and chromatin immunoprecipitation showed VDR and STAT6 colocalisation within the regulatory regions of the affected genes, suggesting that VDR and STAT6 interactome governs epithelial tissue responses to IL-13 signalling. Indeed, VD supplementation reversed IL-13-induced epithelial hyperproliferation, reduced dilated intercellular spaces and barrier permeability, and improved differentiation marker expression (filaggrin, involucrin). In a preclinical model of IL-13-mediated oesophageal allergic inflammation and in human EoE, VD levels inversely associated with severity of oesophageal eosinophilia and epithelial histopathology. CONCLUSIONS: Collectively, these findings identify VD as a natural IL-13 antagonist with capacity to regulate the oesophageal epithelial barrier functions, providing a novel therapeutic entry point for type 2 immunity-related diseases.

Genomic profiling of HMGN1 reveals an association with chromatin at regulatory regions.

The interaction of architectural proteins such as the linker histone H1 and high-mobility-group (HMG) proteins with nucleosomes leads to changes in chromatin structure and histone modifications and alters the cellular transcription profile. The interaction of HMG proteins with chromatin is dynamic. However, it is not clear whether the proteins are constantly and randomly redistributed among all the nucleosomes or whether they preferentially associate with, and turn over at, specific regions in chromatin. To address this question, we examined the genome-wide distribution of the nucleosome binding protein HMGN1 and compared it to that of regulatory chromatin marks. We find that HMGN1 is not randomly distributed throughout the genome. Instead, the protein preferentially localizes to DNase I hypersensitive (HS) sites, promoters, functional enhancers, and transcription factor binding sites. Our results suggest that HMGN1 is part of the cellular machinery that modulates transcriptional fidelity by generating, maintaining, or preferentially interacting with specific sites in chromatin.