Dynamics of chromatin accessibility governing Gd-IgA1 synthesis in B cells associated with IgA nephropathy
Abstract IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. B cells are believed to play a central role in the pathogenesis of IgAN by producing galactose-deficient IgA1 (Gd-IgA1), partly due to aberrant gene expression in B cells. However, the mechanisms underlying the...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-07-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01505-1 |
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| Summary: | Abstract IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. B cells are believed to play a central role in the pathogenesis of IgAN by producing galactose-deficient IgA1 (Gd-IgA1), partly due to aberrant gene expression in B cells. However, the mechanisms underlying the abnormal gene expression in B cells derived from patients with IgAN remain elusive. Here we unveil a broad spectrum of variations in chromatin accessibility in B cells of patients with IgAN through an assay for transposase-accessible chromatin using sequencing (ATAC-seq) by evaluating active DNA regulatory components. A total of 629 genes showed transcriptional alterations associated with differentially chromatin accessibility. The degree of chromatin accessibility was associated with gene expression in peripheral blood B cells of patients with IgAN. Gene Ontology analysis of genes associated with differentially expressed genes and differentially accessible regions revealed enrichment in pathways related to the regulation of transcription. Furthermore, KLF4 was also identified as a key transcription factor promoting the production of IgA1 and Gd-IgA1. In vitro, knockdown of KLF4 suppressed the production of Gd-IgA1 in IgA-secreting cell lines. Through RNA sequencing, this study further showed that KLF4 could regulate the expression of genes related to the intestinal immune network for IgA production. Chromatin immunoprecipitation sequencing combined with RNA sequencing revealed that KLF4 could bind to the IL-6 promoter and regulate its expression. Mechanistically, a luciferase reporter assay verified that KLF4 directly bound to the cis-regulatory element of IL-6 and promoted its expression. The knockdown of KLF4 was shown to alleviate renal lesions and mesangial hypercellularity in IgAN mice. Collectively, the findings from this study elucidated a chromatin-mediated mechanism underlying the differential responses of B cells in IgAN and identified KLF4 as a potential therapeutic target of IgAN. |
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| ISSN: | 2092-6413 |