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，既往的细胞状态可触发表观遗传转录记忆（epigenetic transcriptional memory）：即受抑制的基因会呈现出染色质结构与待命型RNA聚合酶II前起始复合物（poised RNA polymerase II preinitiation complex，RNAPII PIC）的启动子招募层面的有丝分裂可遗传改变，从而增强后续的基因重激活能力。本研究证实，酵母中INO1基因的转录记忆由转录因子Sfl1结合顺式作用的记忆招募序列（Memory Recruitment Sequence）所启动，该结合过程将INO1基因锚定至核周区域。该转录记忆依赖于缺失Spp1亚基的重塑型Set1/COMPASS甲基转移酶（Set1/COMPASS methyltransferase），后者可对组蛋白H3赖氨酸4进行二甲基化修饰（H3K4me2）。H3K4me2修饰会招募SET3C复合物（SET3C complex），该复合物对于维持该组蛋白修饰标记至关重要。最后，活跃状态的INO1基因与不含Cdk8的中介体复合物（Cdk8-Mediator）相结合；而在转录记忆阶段，则是带有Cdk8的中介体复合物（Cdk8+ Mediator）招募缺失Kin28 CTD激酶（Kin28 CTD kinase）的待命型RNAPII PIC。该机制的部分特征可推广至酵母细胞，且在人类细胞中具有保守性。由此可见，COMPASS与中介体复合物（Mediator）通过高度保守的机制被重新赋予功能，以介导表观遗传转录的待命状态形成。