SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.
SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.
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DOI：
10.1016/j.molcel.2016.02.024
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发表时间：
2016-03-17
期刊：
影响因子：
16
通讯作者：
Ahn EY
中科院分区：
文献类型：
--
作者：
Kim JH;Baddoo MC;Park EY;Stone JK;Park H;Butler TW;Huang G;Yan X;Pauli-Behn F;Myers RM;Tan M;Flemington EK;Lim ST;Ahn EY
MLL复合体介导的组蛋白甲基化的失调在与疾病相关的基因表达中起着关键作用，但对调节MLL复合体活性的细胞因子知之甚少。在这里，我们报告SON，以前被称为RNA剪接因子，控制MLL复合物介导的转录起始。SON与转录起始位点附近的DNA结合，与menin相互作用，并抑制MLL复合物组装，导致H3 K4 me 3减少和转录抑制。重要的是，SON的选择性剪接短同种型在急性髓性白血病中显著上调。短同种型与全长SON竞争染色质占用，但缺乏menin结合能力，从而拮抗全长SON在转录抑制中的功能，同时不损害全长SON介导的RNA剪接。此外，SON的短同种型的过表达增强造血祖细胞的再铺板潜力。我们的研究结果将SON定义为MLL-menin相互作用的微调器，并揭示了短SON过表达作为白血病异常转录起始的标志物。
Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy, but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.