Department of Biochemistry, University of Oxford, Oxford, UK.
Nat Commun. 2023 Feb 9;14(1):726. doi: 10.1038/s41467-023-36236-2.
Transcription must be tightly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains rudimentary. Here, by dissecting the function of the SET1 chromatin-modifying complexes that bind to CpG island-associated gene promoters, we discover that they play a specific and essential role in enabling the expression of low to moderately transcribed genes. Counterintuitively, this effect can occur independently of SET1 complex histone-modifying activity and instead relies on an interaction with the RNA Polymerase II-binding protein WDR82. Unexpectedly, we discover that SET1 complexes enable gene expression by antagonising premature transcription termination by the ZC3H4/WDR82 complex at CpG island-associated genes. In contrast, at extragenic sites of transcription, which typically lack CpG islands and SET1 complex occupancy, we show that the activity of ZC3H4/WDR82 is unopposed. Therefore, we reveal a gene regulatory mechanism whereby CpG islands are bound by a protein complex that specifically protects genic transcripts from premature termination, effectively distinguishing genic from extragenic transcription and enabling normal gene expression.
转录必须受到严格控制，以调节基因表达和发育。然而，我们对影响转录的分子机制以及这些机制如何在细胞中协调以确保正常基因表达的理解仍然很初步。在这里，通过剖析与 CpG 岛相关基因启动子结合的 SET1 染色质修饰复合物的功能，我们发现它们在使低至中度转录基因表达方面发挥着特定而必不可少的作用。与直觉相反的是，这种效应可以独立于 SET1 复合物的组蛋白修饰活性发生，而是依赖于与 RNA 聚合酶 II 结合蛋白 WDR82 的相互作用。出乎意料的是，我们发现 SET1 复合物通过拮抗 ZC3H4/WDR82 复合物在 CpG 岛相关基因上的过早转录终止，从而促进基因表达。相比之下，在转录的基因外位点，通常缺乏 CpG 岛和 SET1 复合物占据，我们表明 ZC3H4/WDR82 的活性不受抑制。因此，我们揭示了一种基因调控机制，其中 CpG 岛由一种蛋白质复合物结合，该复合物特异性地保护基因转录本免于过早终止，有效地将基因与基因外转录区分开来，并使正常基因表达成为可能。
