The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth.

双加氧酶的 10-11 易位 (TET) 家族在细胞分裂和谱系规范过程中维持稳定的局部 DNA 去甲基化。作为 TET 酶的主要催化产物，5-羟甲基胞嘧啶以组织依赖性方式选择性富集于特定基因组区域，例如增强子。然而，这种选择性背后的机制仍未解决。在这里，我们揭示了 TET2 内的一个低复杂性插入结构域，有助于其与表观遗传调节剂（如 UTX 和 MLL4）的生物分子缩合。这种共缩合为精确的 DNA 去甲基化营造了良好的染色质环境。破坏低复杂性插入介导的缩合会改变 TET2 的基因组结合，从而导致混杂的 DNA 去甲基化和基因组重组。这些变化影响与白血病发生有关的关键基因的表达，从而抑制白血病细胞增殖。总的来说，这项研究确立了 TET2 缩合在协调精确的 DNA 去甲基化和基因转录以支持肿瘤细胞生长中的关键作用。