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<p>Type 1 diabetes (T1D) is an autoimmune disorder characterized by insulin deficiency and hyperglycemia, driven by environmental insults and epigenetic reprogramming beyond genetic predisposition. Recent evidence suggests that systemic epigenetic dysregulation in T1D influences the differentiation of hematopoietic stem cells (HSCs) towards pro-inflammatory myeloid subsets, such as macrophages and dendritic cells, and compromises lymphoid tolerance, including Treg dysfunction. Mechanistically, perturbations in mitochondrial metabolism in HSCs disrupt the α-ketoglutarate/succinate ratio, which directly regulates TET dioxygenases and DNMTs. Concurrently, dysregulated DNA methylation, histone marks (e.g., H3K27me3), and noncoding RNAs (e.g., MALAT1) connect genetic risk to environmental signals. Clonal hematopoiesis (CHIP), enhanced in T1D by mutations in TET2 and DNMT3A, fuels inflammation by proliferating cytokine-excess HSC clones, thereby accelerating β-cell death. This review provides a comprehensive overview of the current research updates of the disease, including the complex network-mediated epigenetically altered T1D. Moreover, I have explored how epigenetics is involved in hematopoietic dysfunction and how epigenetic reprogramming may underpin these pathologies to mitigate T1D complications and enhance patient outcomes.</p>

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DNMT3A/TET2-mediated epigenetic alteration in Type-1 diabetes dysregulates the haematopoiesis

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Sumit Mallick,
  • Orchid Id

摘要

Type 1 diabetes (T1D) is an autoimmune disorder characterized by insulin deficiency and hyperglycemia, driven by environmental insults and epigenetic reprogramming beyond genetic predisposition. Recent evidence suggests that systemic epigenetic dysregulation in T1D influences the differentiation of hematopoietic stem cells (HSCs) towards pro-inflammatory myeloid subsets, such as macrophages and dendritic cells, and compromises lymphoid tolerance, including Treg dysfunction. Mechanistically, perturbations in mitochondrial metabolism in HSCs disrupt the α-ketoglutarate/succinate ratio, which directly regulates TET dioxygenases and DNMTs. Concurrently, dysregulated DNA methylation, histone marks (e.g., H3K27me3), and noncoding RNAs (e.g., MALAT1) connect genetic risk to environmental signals. Clonal hematopoiesis (CHIP), enhanced in T1D by mutations in TET2 and DNMT3A, fuels inflammation by proliferating cytokine-excess HSC clones, thereby accelerating β-cell death. This review provides a comprehensive overview of the current research updates of the disease, including the complex network-mediated epigenetically altered T1D. Moreover, I have explored how epigenetics is involved in hematopoietic dysfunction and how epigenetic reprogramming may underpin these pathologies to mitigate T1D complications and enhance patient outcomes.