Department of Chemistry, University of Colorado Denver, Denver, CO, 80217-3364, USA.
Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
Nat Commun. 2018 May 25;9(1):2080. doi: 10.1038/s41467-018-04455-7.
Over 80% of diffuse intrinsic pontine gliomas (DIPGs) harbor a point mutation in histone H3.3 where lysine 27 is substituted with methionine (H3.3K27M); however, how the mutation affects kinetics and function of PcG proteins remains elusive. We demonstrate that H3.3K27M prolongs the residence time and search time of Ezh2, but has no effect on its fraction bound to chromatin. In contrast, H3.3K27M has no effect on the residence time of Cbx7, but prolongs its search time and decreases its fraction bound to chromatin. We show that increasing expression of Cbx7 inhibits the proliferation of DIPG cells and prolongs its residence time. Our results highlight that the residence time of PcG proteins directly correlates with their functions and the search time of PcG proteins is critical for regulating their genomic occupancy. Together, our data provide mechanisms in which the cancer-causing histone mutation alters the binding and search dynamics of epigenetic complexes.
超过 80%的弥漫性内在脑桥神经胶质瘤（DIPG）在组蛋白 H3.3 中存在一个点突变，即赖氨酸 27 被甲硫氨酸取代（H3.3K27M）；然而，突变如何影响 PcG 蛋白的动力学和功能仍然难以捉摸。我们证明 H3.3K27M 延长了 Ezh2 的停留时间和搜索时间，但对其与染色质结合的分数没有影响。相比之下，H3.3K27M 对 Cbx7 的停留时间没有影响，但延长了它的搜索时间，并降低了它与染色质结合的分数。我们表明，增加 Cbx7 的表达可抑制 DIPG 细胞的增殖并延长其停留时间。我们的结果强调了 PcG 蛋白的停留时间与其功能直接相关，而 PcG 蛋白的搜索时间对于调节其基因组占据至关重要。总之，我们的数据提供了致癌组蛋白突变改变表观遗传复合物结合和搜索动力学的机制。
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