Investigating the role of dUTX in Drosophila male germ cell differentiation

干细胞具有非凡的能力，可以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。成体干细胞分化以取代受损组织的能力为身体提供了内部修复系统。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。解码控制干细胞维持和分化的分子机制为再生医学的进步和开发基于干细胞的疗法以治疗诸如癌症和组织营养不良等疾病带来了巨大希望。Polycomb Group（PcG）是已知通过其产生抑制性表观遗传标记-组蛋白H3在赖氨酸27处的甲基化（H3 K27 me 3）的能力而充当转录抑制因子的蛋白质家族。这一标志是由Polycomb抑制复合物2（PRC 2）奠定的，并且新出现的图片是PRC 2活性是通过抑制分化基因的表达来维持干细胞增殖状态所必需的。在果蝇雄性生殖系干细胞谱系中，从增殖到分化的转变以PRC 2蛋白水平的降低、TBP相关因子（tTAFs）的睾丸特异性同源物的表达水平的平行增加和终末分化基因启动子上的H3 K27 me 3水平的降低为标志。果蝇X染色体上普遍转录的三肽重复基因（dUTX）的同源物是果蝇唯一的H3 K27 me 3去甲基化酶。它的功能作为一个橡皮擦的抑制性标记和PcG蛋白的拮抗剂表明的作用dUTX在调节从增殖到分化的过渡。此外，哺乳动物UTX最近已显示与Trx的哺乳动物同系物H3 K4 me 3组蛋白甲基转移酶MLL 2相关，这提高了dUTX和TrxG蛋白以及可能的tTAF之间相互作用的可能性。H3 K27 me 3水平的严格控制对于维持增殖向分化转变的严格调节是必要的。dUTX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。这项研究的结果将对癌症生物学和再生医学产生重大影响。

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.