MLL associates specifically with a subset of transcriptionally active target genes
MLL associates specifically with a subset of transcriptionally active target genes
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DOI：
10.1073/pnas.0503630102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Hess, JL
中科院分区：
文献类型：
--
作者：
Milne, TA;Dou, YL;Hess, JL
MILL（混合谱系白血病）是一种组蛋白 H3 Lys-4 特异性甲基转移酶，是 Hox 表达的正调节因子。 MLL 重排和扩增在急性淋巴性和髓性白血病以及骨髓增生异常性疾病中很常见，并且与 Hox 基因表达的异常上调相关。尽管 MLL 在整个造血过程中表达，但 Hox 基因表达在分化过程中急剧下调，表明 MLL 的活性或其与靶启动子的关联必须受到调节。在这里，我们表明 MLL 与活跃转录的基因相关，但在转录下调后不再保持结合。令人惊讶的是，MLL 不仅与启动子区相关，而且分布在基因的整个编码区。 MLL 与 RNA 聚合酶 11 (pol 11) 相互作用，并与 RNA pol 11 共定位于体内活跃转录靶标的子集。 MY 功能丧失会导致 RNA pol 11 分布缺陷。总之，这些结果表明 MLL 和 RNA pol 11 之间的密切关联发生在体内 MLL 靶基因处，这是正常起始和/或转录延伸所需的。
MILL (mixed-lineage leukemia) is a histone H3 Lys-4 specific methyltransferase that is a positive regulator of Hox expression. MLL rearrangements and amplification are common in acute lymphoid and myeloid leukemias and myelodysplastic disorders and are associated with abnormal up-regulation of Hox gene expression. Although MLL is expressed throughout hematopoiesis, Hox gene expression is sharply down-regulated during differentiation, suggesting that either the activity of MLL or its association with target promoters must be regulated. Here we show that MLL associates with actively transcribed genes but does not remain bound after transcriptional down-regulation. Surprisingly, MLL is associated not only with promoter regions but also is distributed across the entire coding regions of genes. MLL interacts with RNA polymerase 11 (pol 11) and colocalizes with RNA pol 11 at a subset of actively transcribed target in vivo. Loss of function MY results in defects in RNA pol 11 distribution. Together the results suggest that an intimate association between MLL and RNA pol 11 occurs at MLL target genes in vivo that is required for normal initiation and/or transcriptional elongation.