Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
Commun Biol. 2024 Sep 10;7(1):1112. doi: 10.1038/s42003-024-06820-3.
Recruitment of non-canonical BCOR-PRC1.1 to non-methylated CpG islands via KDM2B plays a fundamental role in transcription control during developmental processes and cancer progression. However, the mechanism is still largely unknown on how this recruitment is regulated. Here, we unveiled the importance of the Poly-D/E regions within the linker of BCOR for its binding to KDM2B. Interestingly, we also demonstrated that these negatively charged Poly-D/E regions on BCOR play autoinhibitory roles in liquid-liquid phase separation (LLPS) of BCOR/PCGF1. Through neutralizing negative charges of these Poly-D/E regions, Ca not only weakens the interaction between BCOR/PCGF1 and KDM2B, but also promotes co-condensation of the enzymatic core of BCOR-PRC1.1 with KDM2B into liquid-like droplet. Accordingly, we propose that Ca could modulate the compartmentation and recruitment of the enzymatic core of BCOR-PRC1.1 on KDM2B target loci. Thus, our finding advances the mechanistic understanding on how the tethering of BCOR-PRC1.1 enzymatic core to KDM2B is regulated.
非经典的 BCOR-PRC1.1 通过 KDM2B 募集到非甲基化的 CpG 岛，在发育过程和癌症进展中的转录调控中起着至关重要的作用。然而，这种募集是如何被调控的，其机制在很大程度上仍然未知。在这里，我们揭示了 BCOR 连接体中的 Poly-D/E 区域对于其与 KDM2B 结合的重要性。有趣的是，我们还证明了 BCOR 上这些带负电荷的 Poly-D/E 区域在 BCOR/PCGF1 的液-液相分离（LLPS）中发挥自动抑制作用。通过中和这些 Poly-D/E 区域的负电荷，Ca 不仅削弱了 BCOR/PCGF1 与 KDM2B 之间的相互作用，还促进了 BCOR-PRC1.1 的酶核心与 KDM2B 的共凝聚成液态液滴。因此，我们提出 Ca 可以调节 BCOR-PRC1.1 酶核心在 KDM2B 靶基因座上的区室化和募集。因此，我们的发现推进了对 BCOR-PRC1.1 酶核心与 KDM2B 连接的调控机制的理解。
