Abstract
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.
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The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request.
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Funding
This study was supported by Nantong Bureau of Science and Technology [grant numbers MS22022016] and, in part, by Health Commission of Nantong [grant numbers MA2021002]. Additional funding were provided by the Priority Academic Program Development of Nantong Talent Center [grant numbers 2022-Ⅲ-609] and grants from Jiangsu Provincial Research Hospital [grant numbers YJXYY202204].
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Ying Zhao and Zhicheng Tang contributed equally to this manuscript as co-first authors. Professor Weixia Yang participated in the design and revision of the overall research approach, the modification of the manuscript, and the provision of funding.Ying Zhao performed bioinformatics analysis, cell experiments, and wrote the manuscripts. Zhicheng Tang performed the plasmid design, lentivirus constructing and contributing to the manuscript writing. Ying Tao participated in clinical sample collection and cell experiments. Sihui Zhao participated in clinical sample collection, clinical sample processing, and data analysis. Qijie Ding participated in the collection of general information of study subjects and sample collection.
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This study was approved by the Ethics Committee of the Affiliated Hospital of Nantong University(Approval Number: 2021-K085-01) on August 10, 2021. And it was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants or their legal guardians prior to participation in the study. The confidentiality of patient data was ensured throughout the study, and all personal identifiers were removed to protect the privacy of the individuals involved.
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Zhao, Y., Tang, Z., Tao, Y. et al. c-MYC enhances transcription of the type 1 diabetes mellitus associated gene BATF3 via promoter binding. Sci Rep (2026). https://doi.org/10.1038/s41598-026-45579-x
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DOI: https://doi.org/10.1038/s41598-026-45579-x
