Data from: Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory

In yeast and humans, previous experiences can lead to epigenetic transcriptional memory: repressed genes that exhibit mitotically heritable changes in chromatin structure and promoter recruitment of poised RNA polymerase II preinitiation complex (RNAPII PIC), which enhances future reactivation. Here, we show that INO1 memory in yeast is initiated by binding of the Sfl1 transcription factor to the cis-acting Memory Recruitment Sequence, targeting INO1 to the nuclear periphery. Memory requires a remodeled form of the Set1/COMPASS methyltransferase lacking Spp1, which dimethylates histone H3 lysine 4 (H3K4me2). H3K4me2 recruits the SET3C complex, which plays an essential role in maintaining this mark. Finally, while active INO1 is associated with Cdk8- Mediator, during memory, Cdk8+ Mediator recruits poised RNAPII PIC lacking the Kin28 CTD kinase. Aspects of this mechanism are generalizable to yeast and conserved in human cells. Thus, COMPASS and Mediator are repurposed to promote epigenetic transcriptional poising by a highly conserved mechanism.

在酵母与人类细胞中，既往的表观遗传调控事件可引发表观遗传转录记忆：即沉默基因会呈现出有丝分裂可遗传的染色质结构改变，以及 poised RNA聚合酶II预起始复合物（RNAPII PIC）在其启动子区域的招募，该状态可提升后续基因重激活的效率。本研究证实，酵母中的INO1记忆由转录因子Sfl1结合顺式作用的记忆招募序列（Memory Recruitment Sequence）所起始，该结合事件会将INO1靶向锚定至核周区域。该记忆过程依赖于缺失Spp1亚基的重构型Set1/COMPASS甲基转移酶，该酶可催化组蛋白H3赖氨酸4发生二甲基化修饰（H3K4me2）。H3K4me2会招募SET3C复合物，该复合物对维持该表观遗传标记发挥着不可或缺的作用。最后，尽管活性INO1与不含Cdk8亚基的中介体复合物（Cdk8- Mediator）存在关联，但在记忆维持阶段，携带Cdk8亚基的中介体复合物（Cdk8+ Mediator）会招募缺失Kin28 C末端结构域（CTD）激酶的poised RNAPII预起始复合物。该机制的部分特征可推广至酵母，并在人类细胞中高度保守。综上，COMPASS与中介体复合物通过一种高度保守的机制被重新赋予功能，以介导表观遗传转录预准备状态的形成。