Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Mol Cell. 2014 Mar 20;53(6):859-66. doi: 10.1016/j.molcel.2014.02.033.
Why certain point mutations in a general transcription factor are associated with specific forms of cancer has been a major question in cancer biology. Enhancers are DNA regulatory elements that are key regulators of tissue-specific gene expression. Recent studies suggest that enhancer malfunction through point mutations in either regulatory elements or factors modulating enhancer-promoter communication could be the cause of tissue-specific cancer development. In this Perspective, we will discuss recent findings in the identification of cancer-related enhancer mutations and the role of Drosophila Trr and its human homologs, the MLL3 and MLL4/COMPASS-like complexes, as enhancer histone H3 lysine 4 (H3K4) monomethyltransferases functioning in enhancer-promoter communication. Recent genome-wide studies in the cataloging of somatic mutations in cancer have identified mutations in intergenic sequences encoding regulatory elements-and in MLL3 and MLL4 in both hematological malignancies and solid tumors. We propose that cancer-associated mutations in MLL3 and MLL4 exert their properties through the malfunction of Trr/MLL3/MLL4-dependent enhancers.
为什么一般转录因子中的某些点突变与特定形式的癌症有关，这一直是癌症生物学中的一个主要问题。增强子是 DNA 调控元件，是组织特异性基因表达的关键调节剂。最近的研究表明，通过调节元件或调节增强子-启动子通讯的因子中的点突变导致增强子功能障碍，可能是组织特异性癌症发展的原因。在这篇观点文章中，我们将讨论最近在鉴定与癌症相关的增强子突变以及果蝇 Trr 及其人类同源物（MLL3 和 MLL4/COMPASS 样复合物）作为增强子组蛋白 H3 赖氨酸 4（H3K4）单甲基转移酶在增强子-启动子通讯中的作用方面的发现。最近在癌症体细胞突变目录中的全基因组研究已经鉴定出编码调节元件的基因间序列中的突变，以及在血液恶性肿瘤和实体肿瘤中的 MLL3 和 MLL4 中存在突变。我们提出，MLL3 和 MLL4 中的癌症相关突变通过 Trr/MLL3/MLL4 依赖性增强子的功能障碍发挥其作用。
