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 (5hmC) 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 (LCI) domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as ubiquitously transcribedtetratricopeptide repeat on chromosome X (UTX) and mixed-lineage leukemia 4 (MLL4). This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting LCI-mediated condensation alters genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukemogenesis to curtail leukemia cell proliferation. Collectively, this study establishesthe pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumor cell growth.

TET2,phase separation,3D genome,DNA hydroxymethylation