Abstract
STAT3 is highly expressed in aGVHD CD4+ T cells and plays a critical role in inducing or worsening aGVHD. In our preceding studies, DNA hypomethylation in STAT3 promoter was shown to cause high expression of STAT3 in aGVHD CD4+ T cells, and the process could be modulated by HMGB1, but the underlying mechanism remains unclear. TET2, AID, and TDG are indispensable in DNA demethylation; meanwhile, TET2 and AID also serve extremely important roles in immune response. So, we speculated these enzymes involved in the STAT3 promoter hypomethylation induced by HMGB1 in aGVHD CD4+ T cells. In this study, we found that the binding levels of TET2/AID/TDG to STAT3 promoter were remarkably increased in CD4+T cells from aGVHD patients and were significantly negatively correlated with the STAT3 promoter methylation level. Simultaneously, we revealed that HMGB1 could recruit TET2, AID, and TDG to form a complex in the STAT3 promoter region. Interference with the expression of TET2/AID/TDG inhibited the overexpression of STAT3 caused by HMGB1 downregulation of the STAT3 promoter DNA methylation. These data demonstrated a new molecular mechanism of how HMGB1 promoted the expression of STAT3 in CD4+ T cells from aGVHD patients.
Highlights
Allogeneic hematopoietic stem cell transplantation has been recognized as the exclusive treatment to cure hematopoietic malignancies, but acute graft-versushost disease is the primary limitation of the therapy [1,2,3]
We explored the specific process by which HMGB1 increases the expression of Signal transducer and activator of transcription 3 (STAT3) in CD4+ T cells from acute graft-versushost disease (aGVHD) patients and confirmed that HMGB1 could extensively recruit TET2, Activation-induced cytidine deaminase (AID), and thymine-DNA glycosylase (TDG) to bind to STAT3 promoter, which in turn contributed to DNA demethylation of STAT3 promoter
We first explored whether HMGB1, TET2, AID, and TDG could bind to STAT3 promoter using a ChIP-PCR analysis in HMGB1/TET2/AID/TDG overexpressed Jurkat cells
Summary
Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been recognized as the exclusive treatment to cure hematopoietic malignancies, but acute graft-versushost disease (aGVHD) is the primary limitation of the therapy [1,2,3]. Overexpressed STAT3 in aGVHD was found to be tightly linked to various disease progression [7, 8]. Our previous study showed the significantly increased expression of STAT3 was associated with DNA hypomethylation in STAT3 promoter in aGVHD CD4+ T cells. HMGB1 was found to drive DNA demethylation in CD4+ T cells of systemic lupus erythematosus (SLE) patients [11]. DNA methylation is an epigenetic mechanism involved in regulating the gene expression [12]. Our previous study revealed that HMGB1 was markedly overexpressed in CD4+ T cells from aGVHD patients and was positively correlated with the STAT3 promoter DNA methylation level [7]. The exact mechanism by which HMGB1 decreases the DNA methylation level of STAT3 promoter remains unclear
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