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Overexpression of hsa-HLA-DRB1 may play a role in diabetic foot ulcers by regulating miRNA_12118 and FLT-1

ABSTRACT: Introduction: We investigated the role and mechanism of hsa-HLA-DRB1 in the development and progression of diabetic foot ulcers. Methods: High-throughput sequencing was performed on three normal foot trauma tissues and diabetic foot ulcer tissues. The circRNAs with significant differences were identified. The downstream miRNAs were predicted by miRanda and RNAhybrid databases, and the mRNAs were predicted by the TargetScan database. Validation was performed with CCK8, flow cytometry, trabecular scratch assay, tubule generation assay, Western blot, dual luciferase assay, and RT-qPCR. Results: High-throughput sequencing identified 461 significantly different circRNAs, of which 260 were up-regulated and 201 down-regulated. Compared to normal tissue, hsa-HLA-DRB1 was highly expressed in diabetic foot ulcers. The hsa-HLA-DRB1/miRNA_12118/FLT-1 axis was constructed. In vitro, we found that HLA-DRB1 overexpression inhibited cell viability, wound healing, and tubule formation, promoted apoptosis, and enhanced FLT-1 expression in HUVECs. Conclusion: The upregulation of hsa-HLA-DRB1 may promote diabetic foot development by targeting miRNA_12118 and acting on FLT-1. Therefore, our study highlights the key role of the hsa-HLA-DRB1/miRNA_12118/FLT-1 axis in diabetic foot trauma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286165 | GEO | 2025/06/04

REPOSITORIES: GEO

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Project description:Both genetic and environmental factors are implicated in Type 1 Diabetes (T1D). Since environmental factors can trigger epigenetic changes, we hypothesized that variations in histone posttranslational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy non-diabetic controls, and explored their connections to T1D. We used the chromatin-immunoprecipitation-linked-to-microarray approach to profile key histone PTMs, including H3-lysine-4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac) and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac and H4K16Ac at the IDDM1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the IDDM1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon- and TNF-treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response towards external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility. We evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy non-diabetic controls, and explored their connections to T1D. We used the ChIP-chip approach to profile key histone PTMs, including histone H3K4me3, H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac) and H4K16Ac, at genes within the T1D susceptible loci in lymphocytes.

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Overexpression of hsa-HLA-DRB1 may play a role in diabetic foot ulcers by regulating miRNA_12118 and FLT-1

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