Perturbing TET2 Condensation Promotes Aberrant Genome-wide DNA Methylation and Curtails Leukaemia Cell Growth

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2024 Sep 9

PMID 39251719

Authors

Lei Guo

TingTing Hong

Yi-Tsang Lee

Xue Hu

Guokai Pan

Rongjie Zhao

Yuhan Yang

Jingwen Yang

Xiaoli Cai

Logan Rivera

Jie Liang

Rui Wang

Yaling Dou

Srikanth Kodali

Wenbo Li

Leng Han

Bruno Di Stefano

Yubin Zhou

Jia Li

Yun Huang

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Biomolecular condensates in immune cell fate.

Kodali S, Sands C, Guo L, Huang Y, Di Stefano B Nat Rev Immunol. 2025; .

PMID: 39875604 DOI: 10.1038/s41577-025-01130-z.

References

Boija A, Klein I, Young R . Biomolecular Condensates and Cancer. Cancer Cell. 2021; 39(2):174-192. PMC: 8721577. DOI: 10.1016/j.ccell.2020.12.003. View

Mehta S, Zhang J . Liquid-liquid phase separation drives cellular function and dysfunction in cancer. Nat Rev Cancer. 2022; 22(4):239-252. PMC: 10036213. DOI: 10.1038/s41568-022-00444-7. View

Sabari B, DallAgnese A, Boija A, Klein I, Coffey E, Shrinivas K . Coactivator condensation at super-enhancers links phase separation and gene control. Science. 2018; 361(6400). PMC: 6092193. DOI: 10.1126/science.aar3958. View

Li W, Hu J, Shi B, Palomba F, Digman M, Gratton E . Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis. Nat Cell Biol. 2020; 22(8):960-972. PMC: 7425812. DOI: 10.1038/s41556-020-0550-8. View

Shi B, Li W, Song Y, Wang Z, Ju R, Ulman A . UTX condensation underlies its tumour-suppressive activity. Nature. 2021; 597(7878):726-731. PMC: 9008583. DOI: 10.1038/s41586-021-03903-7. View

Ahn J, Davis E, Daugird T, Zhao S, Quiroga I, Uryu H . Phase separation drives aberrant chromatin looping and cancer development. Nature. 2021; 595(7868):591-595. PMC: 8647409. DOI: 10.1038/s41586-021-03662-5. View

Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj A, Kim H . Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell. 2015; 163(1):123-33. PMC: 5149108. DOI: 10.1016/j.cell.2015.09.015. View

Gopal P, Nirschl J, Klinman E, Holzbaur E . Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons. Proc Natl Acad Sci U S A. 2017; 114(12):E2466-E2475. PMC: 5373408. DOI: 10.1073/pnas.1614462114. View

Terlecki-Zaniewicz S, Humer T, Eder T, Schmoellerl J, Heyes E, Manhart G . Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression. Nat Struct Mol Biol. 2021; 28(2):190-201. PMC: 7116736. DOI: 10.1038/s41594-020-00550-w. View

10.

Tahiliani M, Koh K, Shen Y, Pastor W, Bandukwala H, Brudno Y . Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324(5929):930-5. PMC: 2715015. DOI: 10.1126/science.1170116. View

11.

Ito S, Shen L, Dai Q, Wu S, Collins L, Swenberg J . Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011; 333(6047):1300-3. PMC: 3495246. DOI: 10.1126/science.1210597. View

12.

He Y, Li B, Li Z, Liu P, Wang Y, Tang Q . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011; 333(6047):1303-7. PMC: 3462231. DOI: 10.1126/science.1210944. View

13.

Fang S, Li J, Xiao Y, Lee M, Guo L, Han W . Tet inactivation disrupts YY1 binding and long-range chromatin interactions during embryonic heart development. Nat Commun. 2019; 10(1):4297. PMC: 6754421. DOI: 10.1038/s41467-019-12325-z. View

14.

Hon G, Song C, Du T, Jin F, Selvaraj S, Lee A . 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol Cell. 2014; 56(2):286-297. PMC: 4319980. DOI: 10.1016/j.molcel.2014.08.026. View

15.

Lio C, Zhang J, Gonzalez-Avalos E, Hogan P, Chang X, Rao A . Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility. Elife. 2016; 5. PMC: 5142813. DOI: 10.7554/eLife.18290. View

16.

Cui X, Nie J, Ku J, Dougherty U, West-Szymanski D, Collin F . A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation. Nat Commun. 2020; 11(1):6161. PMC: 7710742. DOI: 10.1038/s41467-020-20001-w. View

17.

Huang Y, Rao A . Connections between TET proteins and aberrant DNA modification in cancer. Trends Genet. 2014; 30(10):464-74. PMC: 4337960. DOI: 10.1016/j.tig.2014.07.005. View

18.

Ko M, Huang Y, Jankowska A, Pape U, Tahiliani M, Bandukwala H . Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010; 468(7325):839-43. PMC: 3003755. DOI: 10.1038/nature09586. View

19.

Couronne L, Bastard C, Bernard O . TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med. 2012; 366(1):95-6. DOI: 10.1056/NEJMc1111708. View

20.

Busque L, Patel J, Figueroa M, Vasanthakumar A, Provost S, Hamilou Z . Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012; 44(11):1179-81. PMC: 3483435. DOI: 10.1038/ng.2413. View