H3K4 甲基转移酶 SETD1A 在发育和癌症中发挥着重要作用。然而，涉及 SETD1A 染色质结合的重要成分仍不清楚。在这里，我们发现 BOD1L 在人类癌细胞系中表现出最高相关的 SETD1A 共依赖性。 BOD1L 敲除可在体外和体内减少白血病细胞，并模仿 SETD1A 敲除细胞中观察到的转录谱。 BOD1L 的缺失立即减少了转录起始位点 (TSS) 上的 SETD1A 分布，诱导转录延伸缺陷，并增加了 TSS 处的 RNA 聚合酶 II 含量；然而，它并没有减少H3K4me3。 BOD1L的Shg1结构域具有DNA结合能力，该结构域中的色氨酸残基（W104）通过与SETD1A FLOS结构域的结合将SETD1A募集至染色质。此外，BOD1L-SETD1A 复合物与转录调节因子（包括 E2F）相关。这些结果表明，BOD1L 介导染色质和 SETD1A，并调节转录中 SETD1A 的非规范功能。© 作者 2024。由牛津大学出版社代表 Nucleic Acids Research 出版。

The H3K4 methyltransferase SETD1A plays an essential role in both development and cancer. However, essential components involved in SETD1A chromatin binding remain unclear. Here, we discovered that BOD1L exhibits the highest correlated SETD1A co-dependency in human cancer cell lines. BOD1L knockout reduces leukemia cells in vitro and in vivo, and mimics the transcriptional profiles observed in SETD1A knockout cells. The loss of BOD1L immediately reduced SETD1A distribution at transcriptional start sites (TSS), induced transcriptional elongation defect, and increased the RNA polymerase II content at TSS; however, it did not reduce H3K4me3. The Shg1 domain of BOD1L has a DNA binding ability, and a tryptophan residue (W104) in the domain recruits SETD1A to chromatin through the association with SETD1A FLOS domain. In addition, the BOD1L-SETD1A complex associates with transcriptional regulators, including E2Fs. These results reveal that BOD1L mediates chromatin and SETD1A, and regulates the non-canonical function of SETD1A in transcription.© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.