Abstract
BackgroundTranscription factor B cell lymphoma 6 (BCL6) is a master regulator of T follicular helper (Tfh) cells, which play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanisms by which BCL6 expression is regulated are poorly understood. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important epigenetic factor that regulates DNA methylation and histone modifications. In the present study, we assessed whether UHRF1 can regulate BCL6 expression and influence the differentiation and proliferation of Tfh cells.ResultsCompared to healthy controls, the mean fluorescence intensity of UHRF1 (UHRF1-MFI) in Tfh cells from SLE patients was significantly downregulated, whereas that of BCL6 (BCL6-MFI) was significantly upregulated. In vitro, UHRF1 knockdown led to BCL6 overexpression and promoted Tfh cell differentiation. In contrast, UHRF1 overexpression led to BCL6 downregulation and decreased Tfh cell differentiation. In vivo, conditional UHRF1 gene knockout (UHRF1-cKO) in mouse T cells revealed that UHRF1 depletion can enhance the proportion of Tfh cells and induce an augmented GC reaction in mice treated with NP-keyhole limpet hemocyanin (NP-KLH). Mechanistically, UHRF1 downregulation can decrease DNA methylation and H3K27 trimethylation (H3K27me3) levels in the BCL6 promoter region of Tfh cells.ConclusionsOur results demonstrated that UHRF1 downregulation leads to increased BCL6 expression by decreasing DNA methylation and H3K27me3 levels, promoting Tfh cell differentiation in vitro and in vivo. This finding reveals the role of UHRF1 in regulating Tfh cell differentiation and provides a potential target for SLE therapy.
Highlights
Transcription factor B cell lymphoma 6 (BCL6) is a master regulator of T follicular helper (Tfh) cells, which play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE)
UHRF1 expression is reduced in circulating follicular helper T cells isolated from peripheral blood mononuclear cells (PBMCs) of SLE patients We first measured CD4, programmed cell death-1 (PD1), CXC-chemokine receptor 5 (CXCR5) expression in PBMCs by flow cytometry (FCM), the results of which showed that the Tfh cell proportion was significantly higher in SLE patients than healthy controls (Fig. 1a), consistent with our previous findings[30]
The results showed that the UHRF1-mean fluorescence intensity (MFI) was significantly lower in Tfh cells isolated from SLE patients than in those isolated from healthy controls (Fig. 1b)
Summary
Transcription factor B cell lymphoma 6 (BCL6) is a master regulator of T follicular helper (Tfh) cells, which play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). The mechanisms by which BCL6 expression is regulated are poorly understood. We assessed whether UHRF1 can regulate BCL6 expression and influence the differentiation and proliferation of Tfh cells. Transcription factor BCL6, which is considered to be a master regulator of Tfh cells, controls Tfh cell differentiation and function [14]. Increasing evidence as shown that the proportion of Tfh cells is increased in SLE patients, indicating that they play a crucial role in the dysregulated antibody responses associated with SLE [15,16,17]. The mechanisms by which the aberrant differentiation of Tfh cells is regulated remain poorly understood
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