{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTET1 is a 2‑oxoglutarate– (2OG–) and Fe(II)–dependent dioxygenase that initiates active DNA demethylation by oxidizing 5‑methylcytosine (5mC) into 5‑hydroxymethylcytosine (5hmC), a modification critical for regulating gene expression programs in embryonic stem cells and during development. This enzymatic activity, which can be influenced by metabolic changes and mutations (for example, those affecting cofactors or downstream oxidation intermediates), sets the stage for subsequent chromatin re‐organization and promotes demethylation via mechanisms including deamination and base excision repair. Collectively, these studies underscore TET1’s fundamental role in establishing and maintaining an epigenetically permissive state at CpG‑rich regulatory elements."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer, TET1 exhibits a context‑dependent duality. In many solid tumors—including colorectal, gastric, and breast cancers—a downregulation of TET1 and a loss of 5hmC are associated with hypermethylation and silencing of tumor suppressor genes (such as PTEN and inhibitors of metalloproteinases), thereby promoting increased cell proliferation, invasion, and metastasis; restoration of TET1 activity can reverse these aberrant methylation patterns and hinder tumor progression. In contrast, in MLL‑rearranged leukemias TET1 is aberrantly upregulated, where it cooperates with fusion proteins to stimulate oncogenic programs (for example, through the activation of HOXA9, MEIS1, and related targets), thereby contributing directly to leukemogenesis. These findings illustrate that whether acting as a tumor suppressor or as an oncogenic driver, TET1’s regulation of DNA methylation is a pivotal determinant in tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its core demethylase function in shaping the epigenetic landscape, TET1 is dynamically regulated by environmental and intracellular signals such as hypoxia, inflammatory cytokines, and metabolic stress, which in turn modulate its impact on transcriptional networks and cell fate decisions. Hypoxic conditions, for instance, can lead to TET1 upregulation and redistribution of 5hmC to hypoxia‐responsive gene promoters, while in other cellular settings diminished TET1 levels can alter NF‑κB signaling and contribute to chemoresistance. Emerging data also implicate interactions with specific microRNAs and post‑translational modifications as additional layers controlling TET1 activity, emphasizing its broad role in genome integrity, alternative splicing regulation, and even in modulating immune responses. These multifaceted insights position TET1 as both a critical mediator of normal cellular function and a potential therapeutic target in diverse disease contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mamta Tahiliani, Kian Peng Koh, Yinghua Shen, et al. 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