Development：研究果蝇基因为开发治疗人类癌症新药提供思路

近日，来自罗耀拉大学的研究者利用果蝇的基因开发出了一种新型的治疗癌症的武器。研究者发现果蝇的某些基因和人类两个癌症发育相关的基因具有一定的相似性。随着果蝇的基因不断变化，原先的一个基因变为两个，这对于我们研究其功能提供了便利，这将对于研发抗癌新药提供帮助。相关研究成果刊登在了国际杂志Development上。

正常细胞发育的过程中可以分裂为许多特殊类型的细胞，比如骨细胞和肌肉细胞等，这个分类过程是受基因和激素互相协同调节的，这些基因中的两个为MLL1和MLL2。相反癌症细胞的分裂却不受控制。

从2010年开始，研究者发现一些癌症，如非霍奇金淋巴瘤、结直肠癌等癌症和基因MLL2、MLL3的突变相关，而且也有证据显示，这两个基因的突变和乳腺癌、前列腺癌相关。这两个基因非常相似，类似于彼此，每一个基因均有15，000个碱基对，是标准基因中碱基对数量的10倍以上。因为这两个基因如此的复杂，因此对于研究者研究来说有一定难度。

在果蝇中，相似基因MLL1和MLL2可以分裂为两个基因TRR和CMI，每一个携带有正常基因的调节信息。对果蝇中相似基因的分析使得我们可以更深入地对人类基因MLL1和MLL2进行研究分析。研究者Dingwall通过诱导果蝇中相似基因的突变、检测其突变后效应来研究基因的功能，这将为我们理解MLL1和MLL2突变可以诱发癌症细胞的无限制生长提供了基础。

这项研究由美国国家科学基金会等机构给予资助。

编译自：Quirky Fruit Fly Gene Could Point Way to New Cancer Drugs

编译者：天使托

doi:10.1242/dev.076687
PMC:
PMID:

Histone recognition and nuclear receptor co-activator functions of Drosophila Cara Mitad, a homolog of the N-terminal portion of mammalian MLL2 and MLL3

Chhavi Chauhan1,*, Claudia B. Zraly1,*,‡, Megan Parilla1, Manuel O. Diaz1,2 and Andrew K. Dingwall1,3,‡

MLL2 and MLL3 histone lysine methyltransferases are conserved components of COMPASS-like co-activator complexes. In vertebrates, the paralogous MLL2 and MLL3 contain multiple domains required for epigenetic reading and writing of the histone code involved in hormone-stimulated gene programming, including receptor-binding motifs, SET methyltransferase, HMG and PHD domains. The genes encoding MLL2 and MLL3 arose from a common ancestor. Phylogenetic analyses reveal that the ancestral gene underwent a fission event in some Brachycera dipterans, including Drosophila species, creating two independent genes corresponding to the N- and C-terminal portions. In Drosophila, the C-terminal SET domain is encoded by trithorax-related (trr), which is required for hormone-dependent gene activation. We identified the cara mitad (cmi) gene, which encodes the previously undiscovered N-terminal region consisting of PHD and HMG domains and receptor-binding motifs. The cmi gene is essential and its functions are dosage sensitive. CMI associates with TRR, as well as the EcR-USP receptor, and is required for hormone-dependent transcription. Unexpectedly, although the CMI and MLL2 PHDf3 domains could bind histone H3, neither showed preference for trimethylated lysine 4. Genetic tests reveal that cmi is required for proper global trimethylation of H3K4 and that hormone-stimulated transcription requires chromatin binding by CMI, methylation of H3K4 by TRR and demethylation of H3K27 by the demethylase UTX. The evolutionary split of MLL2 into two distinct genes in Drosophila provides important insight into distinct epigenetic functions of conserved readers and writers of the histone code.