Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation.

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-01 DOI:10.1016/j.jbc.2023.105204
Kevin E W Namitz, Scott A Showalter, Michael S Cosgrove
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Abstract

Enzymes that regulate the degree of histone H3 lysine 4 (H3K4) methylation are crucial for proper cellular differentiation and are frequently mutated in cancer. The Mixed lineage leukemia (MLL) family of enzymes deposit H3K4 mono-, di-, or trimethylation at distinct genomic locations, requiring precise spatial and temporal control. Despite evidence that the degree of H3K4 methylation is controlled in part by a hierarchical assembly pathway with key subcomplex components, we previously found that the assembled state of the MLL1 core complex is not favored at physiological temperature. To better understand this paradox, we tested the hypothesis that increasing the concentration of subunits in a biomolecular condensate overcomes this thermodynamic barrier via mass action. Here, we demonstrate that MLL1 core complex phase separation stimulates enzymatic activity up to 60-fold but not primarily by concentrating subunits into droplets. Instead, we found that stimulated activity is largely due to the formation of an altered oligomeric scaffold that greatly reduces substrate Km. We posit that phase separation-induced scaffolding of the MLL1 core complex is a potential "switch-like" mechanism for spatiotemporal control of H3K4 methylation through the rapid formation or dissolution of biomolecular condensates within RNA Pol II transcription factories.

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相分离促进MLL1核心复合物的高活性寡聚支架用于调节组蛋白H3K4甲基化。
调节组蛋白H3赖氨酸4(H3K4)甲基化程度的酶对于正确的细胞分化至关重要,并且在癌症中经常发生突变。混合谱系白血病(MLL)家族的酶在不同的基因组位置沉积H3K4单、二或三甲基化,需要精确的空间和时间控制。尽管有证据表明H3K4甲基化的程度部分由具有关键亚复合体组分的分级组装途径控制,但我们之前发现,MLL1核心复合体的组装状态在生理温度下并不有利。为了更好地理解这一悖论,我们测试了一种假设,即增加生物分子冷凝物中亚基的浓度可以通过质量作用克服这一热力学障碍。在这里,我们证明了MLL1核心复合物相分离刺激酶活性高达60倍,但主要不是通过将亚基浓缩成液滴。相反,我们发现受刺激的活性很大程度上是由于改变的低聚支架的形成,该支架大大降低了底物Km。我们认为,相分离诱导的MLL1核心复合物的支架是一种潜在的“开关样”机制,通过在RNA Pol II转录工厂内快速形成或溶解生物分子缩合物来时空控制H3K4甲基化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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