美国德州农工大学黄韵、周育斌和广州医科大学李佳课题组合作取得一项新突破。他们的最新研究发现扰乱TET2凝聚，会导致全基因组DNA甲基化异常并抑制白血病细胞生长。该研究于2024年9月9日发表于国际学术期刊《自然-细胞生物学》杂志。

研究人员发现TET2中存在一个低复杂性插入结构域，它能促进TET2与表观遗传调节因子（如UTX和MLL4）的生物分子凝聚。这种共凝聚为DNA的精确去甲基化创造了有利的染色质环境。破坏低复杂性插入介导的凝聚会改变TET2在基因组上的结合，从而导致DNA去甲基化紊乱和基因组重组。

这些变化会影响与白血病发生有关的关键基因表达，从而抑制白血病细胞的增殖。总之，该研究揭示了TET2凝聚在协调DNA去甲基化和基因转录以维持肿瘤细胞生长过程中的关键作用。

据介绍，10-11易位（TET）双加氧酶家族在细胞分裂和品系分化过程中维持局部DNA去甲基化稳定。作为TET酶的主要催化产物，5-羟甲基胞嘧啶以组织依赖的方式选择性地在特定基因组区域富集，如增强子。然而，这种选择性的内在机制仍然未知。

附：英文原文

Title: Perturbing TET2 condensation promotes aberrant genome-wide DNA methylation and curtails leukaemia cell growth

Author: Guo, Lei, Hong, Tingting, Lee, Yi-Tsang, Hu, Xue, Pan, Guokai, Zhao, Rongjie, Yang, Yuhan, Yang, Jingwen, Cai, Xiaoli, Rivera, Logan, Liang, Jie, Wang, Rui, Dou, Yaling, Kodali, Srikanth, Li, Wenbo, Han, Leng, Di Stefano, Bruno, Zhou, Yubin, Li, Jia, Huang, Yun

Issue&Volume: 2024-09-09

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.

DOI: 10.1038/s41556-024-01496-7

Source: https://www.nature.com/articles/s41556-024-01496-7