Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
Mol Cell Biol. 2013 May;33(9):1702-10. doi: 10.1128/MCB.01585-12. Epub 2013 Mar 4.
The human MLL genes (MLL1 to MLL4) and their Drosophila orthologs, trithorax (trx) and trithorax related (trr), encode proteins capable of methylating histone H3 on lysine 4. MLL1 and MLL2 are most similar to trx, while MLL3 and MLL4 are more closely related to trr. Several MLL genes are mutated in human cancers, but how these proteins regulate cell proliferation is not known. Here we show that trr mutant cells have a growth advantage over their wild-type neighbors and display changes in the levels of multiple proteins that regulate growth and cell division, including Notch, Capicua, and cyclin B. trr mutant clones display markedly reduced levels of H3K4 monomethylation without obvious changes in the levels of H3K4 di- and trimethylation. The trr mutant phenotype resembles that of Utx, which encodes a H3K27 demethylase, consistent with the observation that Trr and Utx are found in the same protein complex. In contrast to the overgrowth displayed by trr mutant tissue, trx clones are underrepresented, express low levels of the antiapoptotic protein Diap1, and exhibit only modest changes in global levels of H3K4 methylation. Thus, in Drosophila eye imaginal discs, Trr, likely functioning together with Utx, restricts tissue growth. In contrast, Trx appears to promote cell survival.
人类的 MLL 基因（MLL1 到 MLL4）及其果蝇直系同源物，trithorax（trx）和 trithorax 相关（trr），编码能够将组蛋白 H3 赖氨酸 4 甲基化的蛋白质。MLL1 和 MLL2 与 trx 最相似，而 MLL3 和 MLL4 与 trr 更相似。几种 MLL 基因在人类癌症中发生突变，但这些蛋白质如何调节细胞增殖尚不清楚。在这里，我们表明 trr 突变细胞相对于其野生型相邻细胞具有生长优势，并显示出多种调节生长和细胞分裂的蛋白质水平发生变化，包括 Notch、Capicua 和细胞周期蛋白 B。trr 突变克隆显示 H3K4 单甲基化水平明显降低，而 H3K4 二甲基化和三甲基化水平没有明显变化。trr 突变表型类似于编码 H3K27 去甲基酶的 Utx，这与 Trr 和 Utx 存在于同一蛋白复合物的观察结果一致。与 trr 突变组织显示的过度生长相反，trx 克隆的数量较少，抗凋亡蛋白 Diap1 的表达水平较低，并且 H3K4 甲基化的总体水平仅发生适度变化。因此，在果蝇眼 imaginal 盘组织中，Trr 可能与 Utx 一起限制组织生长。相比之下，Trx 似乎促进细胞存活。
