Investigating the role of dUTX in Drosophila male germ cell differentiation

干细胞具有非凡的能力进行不对称有丝分裂产生两个不同的子细胞。一个子细胞保持干细胞的特性和再生能力，而另一个子细胞分化以补充专门的细胞类型。成体干细胞分化以替代受损组织的能力为机体提供了一个内部修复系统。然而，控制干细胞如何产生终末分化细胞的确切机制还不是很清楚。破解控制干细胞维持和分化的分子机制对再生医学的进步和开发基于干细胞的治疗方法来治疗癌症和组织营养不良等疾病具有很大的希望。Polycomb Group （PcG）是一个已知的转录抑制蛋白家族，通过其产生抑制表观遗传标记-赖氨酸27处组蛋白H3甲基化（H3K27me3）的能力而发挥转录抑制作用。这一标记是由Polycomb suppression Complex 2 （PRC2）奠定的，并且新出现的图像表明，PRC2的活性是通过抑制分化基因的表达来维持干细胞的增殖状态所必需的。在果蝇雄性生殖系干细胞谱系中，从增殖到分化的转变标志着PRC2蛋白水平的降低，tbp相关因子（tTAFs）睾丸特异性同源物表达水平的平行增加，以及终端分化基因启动子上H3K27me3水平的降低。果蝇在哺乳动物X染色体上普遍转录的四元肽重复基因（dUTX）是果蝇唯一的H3K27me3去甲基化酶。其作为抑制标记的擦除剂和PcG蛋白拮抗剂的功能表明，dUTX在从增殖到分化的过渡调节中发挥作用。此外，哺乳动物UTX最近被证明与Trx的哺乳动物同源物H3K4me3组蛋白甲基转移酶MLL2相关，这提高了dUTX和TrxG蛋白以及可能的tTAFs之间相互作用的可能性。严格控制H3K27me3水平对于维持增殖向分化过渡的严格调控是必要的。使UTX失活的突变与人类癌症有关；因此，dUTX在逆转PcG沉默中的潜在作用使其成为癌症治疗中有希望的靶点。本研究结果将对癌症生物学和再生医学具有重要意义。

Stem cells have the remarkable ability to undergo asymmetric mitotic divisions that produce two distinct daughter cells. One daughter maintains the stem cell properties and regenerative potency while the other differentiates to replenish specialized cell types. The ability of adult stem cells to differentiate to replace damaged tissues provides the body with an internal repair system. However, the exact mechanisms that govern how a stem cell gives rise to a terminally differentiated cell are not very well understood. Decoding the molecular mechanisms governing stem cell maintenance and differentiation holds great promise for the advancement of regenerative medicine and for developing stem cell based therapies to treat diseases such as cancers and tissue dystrophy. Polycomb Group (PcG) is a family of proteins that are known to act as transcription repressors through their ability to generate a repressive epigenetic mark - methylation of histone H3 at lysine 27 (H3K27me3). This mark is laid down by the Polycomb Repressive Complex 2 (PRC2) and the emerging picture is that PRC2 activity is required to maintain the proliferative state of stem cells by repressing the expression of differentiation genes. In the Drosophila male germline stem cell lineage, the shift from proliferation to differentiation is marked by a decrease in PRC2 protein levels, a parallel increase in the expression levels of testis-specific homologs of TBP-associated factor (tTAFs) and a decrease in H3K27me3 levels on the promoters of terminal differentiation genes. Drosophila homolog of mammalian ubiquitously transcribed tetratricopeptiderepeat gene on the X chromosome (dUTX) is the sole fly H3K27me3 demethylase. Its function as an eraser of a repressive mark and an antagonist of PcG proteins suggests a role for dUTX in the regulation of the transition from proliferation to differentiation. Moreover, mammalian UTX has been recently shown to associate with the mammalian homolog of Trx, H3K4me3 histone methyltransferase MLL2 which raises the possibility of an interaction between dUTX and TrxG proteins and possibly the tTAFs. Firm control of H3K27me3 levels is necessary to maintain the tight regulation of the proliferation-to-differentiation transition. Mutations that inactivate UTX have been linked to human cancer; therefore, the potential role of dUTX in the reversal of PcG silencing makes it a promising target in cancer therapeutics. Results from this study will have significant implications on cancer biology and regenerative medicine.