Perturbation of TET2 condensation induces genome-wide promiscuous DNA hypomethylation and curtails leukemia cell growth

The Ten-Eleven Translocation (TET)-mediated DNA modification pathway is intimately involved in transcriptional regulation. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine (5hmC) is enriched at selected enhancers in a tissue specific manner, with the underlying mechanism yet to be clarified. Here, we report a low complexity insert (LCI) domain within the TET2 catalytic domain that facilitates TET2 condensation and enables its precise chromatin binding, which leads to DNA demethylation at specific genomic regions. Perturbation of TET2 condensation results in promiscuous DNA demethylation that accounts for large-scale topological changes in the genome, which alter the expression of genes that associated with patient survival and ultimately suppresses leukemia cell growth both in vitro and in vivo. Our study illuminates a previously neglected liquid-like condensation property of TET2 in gene regulation and explores the potential of targeting biomolecular condensation of epigenetic enzymes for effective cancer intervention. Overall design: Comparative gene expression profiling analysis of RNA-seq data for MOLM13 cells expressing human TET2 CD and TET2-CD?LCI .DNA from mESC or MOLM13 cells expressing TET2-CD and TET2-CD?LCI were extracted and subjected to WGBS. We generated mouse embryonic stem cells (mESCs) that stably expressed DamID only, TET2CD-Dam or TET2CD?LCI-Dam. DNA from mESC or MOLM13 cells expressing TET2-CD and TET2-CD?LCI were extracted and subjected to CMS-IP. Mouse stem cells (mESCs) 5hmC mapping (CMSIP).