Unique and Shared Roles for Histone H3K36 Methylation States in Transcription Regulation Functions

Set2 co-transcriptionally methylates lysine 36 of histone H3 (H3K36), producing mono-, di-, and trimethylation (H3K36me1/2/3). These modifications recruit or repel chromatin effector proteins important for transcriptional fidelity, mRNA splicing, and DNA repair. However, it was not known whether the different methylation states of H3K36 have distinct biological functions. Here, we use engineered forms of Set2 that produce different lysine methylation states to identify unique and shared functions for H3K36 modifications. Although H3K36me1/2 and H3K36me3 are functionally redundant in many SET2 deletion phenotypes, we found that H3K36me3 has a unique function related to Bur1 kinase activity and FACT (facilitates chromatin transcription) complex function. Further, during nutrient stress, either H3K36me1/2 or H3K36me3 represses high levels of histone acetylation and cryptic transcription that arises from within genes. Our findings uncover the potential for the regulation of diverse chromatin functions by different H3K36 methylation states.Set2可共转录修饰组蛋白H3的赖氨酸36位点（H3K36），生成单甲基化、二甲基化与三甲基化产物（H3K36me1/2/3）。此类修饰可招募或排斥与转录保真度、mRNA剪接及DNA修复密切相关的染色质效应蛋白。然而此前尚不明确H3K36的不同甲基化状态是否具备独特的生物学功能。本研究通过构建可产生不同赖氨酸甲基化状态的工程化Set2变体，鉴定出H3K36修饰所独有的及共有的生物学功能。尽管在诸多Set2缺失表型中，H3K36me1/2与H3K36me3功能冗余，但我们发现H3K36me3存在与Bur1激酶活性及FACT（facilitates chromatin transcription）复合体功能相关的独有功能。此外，在营养应激过程中，H3K36me1/2或H3K36me3均可抑制高水平的组蛋白乙酰化以及基因内部产生的隐蔽转录。本研究揭示了不同H3K36甲基化状态调控多样染色质功能的潜在潜力。