莫纳什大学Omer Gilan课题组宣布他们的论文发现了DOT1L通过PRC1.1拮抗提供转录记忆。2026年2月3日出版的《自然—细胞生物学》杂志发表了这项成果。

在这里，课题组研究人员确定了非规范Polycomb抑制复合体1.1 （PRC1.1）在介导细胞对DOT1L和Menin抑制剂的反应中的关键作用。Menin抑制诱导H2AK119ub的PRC1.1依赖性沉积以沉默MLL-FP靶点，而DOT1L抑制导致H2AK119ub在全基因组范围内增加。小组发现，PRC1.1活性的增强是由DOT1L介导的H3K79甲基化的逐渐丧失引起的，与MLL-FP位移或转录抑制无关。这种调控串扰在不同的细胞类型中是保守的，并由H3K79甲基化和PRC1活性之间的直接生化拮抗作用驱动。总之，他们的发现确定了DOT1L是白血病中转录记忆的一个组成部分，并表明它是平衡MLL-Polycomb轴的反作用力的缺失环节。

据了解，DOT1L和Menin是白血病中MLL-Polycomb蛋白（MLL-FPs）致癌活性的重要辅助因子。然而，支撑其抑制剂治疗效果的机制仍不清楚。

附：英文原文

Title: DOT1L provides transcriptional memory through PRC1.1 antagonism

Author: Neville, Daniel, Ferguson, Daniel T., Heikamp, Emily B., Lai, Zhihao, Magor, Graham W., Lam, Charlene, Dobbs, Olivia G., Levina, Vita, Knezevic, Kathy, The, James J., Alex, Shania, Suits, Stephen C., Rumler, Bradon, Uckelmann, Michael, Talarmain, Laure, Lam, Enid Y. N., Perkins, Andrew C., Armstrong, Scott A., Bell, Charles C., Davidovich, Chen, Gilan, Omer

Issue&Volume: 2026-02-03

Abstract: DOT1L and Menin are essential cofactors for the oncogenic activity of MLL fusion proteins (MLL-FPs) in leukaemia. However, the mechanisms underpinning the therapeutic effects of their inhibitors remain unclear. Here we identify a critical role for the non-canonical Polycomb repressive complex 1.1 (PRC1.1) in mediating the cellular responses to DOT1L and Menin inhibitors. Menin inhibition induces PRC1.1-dependent deposition of H2AK119ub to silence a subset of MLL-FP targets, whereas DOT1L inhibition results in a genome-wide increase in H2AK119ub. We show that enhanced PRC1.1 activity arises specifically from the progressive loss of DOT1L-mediated H3K79 methylation, independent of MLL-FP displacement or transcriptional repression. This regulatory crosstalk is conserved across cell types and is driven by direct biochemical antagonism between H3K79 methylation and PRC1 activity. Together, our findings establish DOT1L as a component of transcriptional memory co-opted in leukaemia and suggest it serves as the missing link balancing the opposing forces of the MLL–Polycomb axis.

DOI: 10.1038/s41556-025-01859-8

Source: https://www.nature.com/articles/s41556-025-01859-8