The basic leucine zipper ATF-like transcription factor 3 (BATF3) has been implicated in the pathogenesis of type 1 diabetes mellitus (T1DM), where it may influence immune regulation and pancreatic β-cell homeostasis. Nevertheless, the upstream molecular mechanisms governing BATF3 expression remain largely undefined. Bioinformatic analyses of GEO and UCSC databases were conducted to identify transcription factors potentially regulating BATF3 (GEO: GSE9006 PBMC microarray; newly diagnosed T1D, n = 43; healthy controls, n = 24). Clinical samples (PBMC, n = 30) from T1DM patients and healthy controls were analyzed by qPCR to assess BATF3 and candidate transcription factor expression. Lentiviral transduction and siRNA-mediated knockdown were applied to examine BATF3 regulation and its impact on CD8⁺ T-cell function. Transcription factor-promoter interactions were validated using dual-luciferase reporter assays and ChIP-qPCR. EGR1, EGR2, EGR3, and c-MYC were identified as differentially expressed transcription factors in GSE9006, with c-MYC emerging as the central regulator. Clinical analysis demonstrated significantly elevated expression of c-MYC and BATF3 in T1DM patients compared with healthy controls (n = 30, p < 0.05). In vitro assays confirmed that c-MYC binds to the BATF3 promoter region approximately 1-2 kb upstream of the transcription start site, thereby promoting BATF3 transcription, enhancing CD8⁺ T-cell proliferation, and inhibiting apoptosis (CD8⁺ T cells isolated from PBMCs of healthy children). ChIP-qPCR further localized the primary c-MYC binding site to the - 1,214 to - 1,203 bp region relative to the BATF3 transcription start site. c-MYC, a critical regulator of BATF3, is markedly elevated in T1DM patients. By driving BATF3 transcription, it promotes CD8⁺ T-cell expansion and limits apoptosis, jointly contributing to pediatric T1DM pathogenesis. These observations highlight the c-MYC-BATF3 axis as a mechanistic pathway relevant to pediatric T1DM and a potential biomarker framework.
Zhao et al. (Wed,) studied this question.