Investigating the role of dUTX in Drosophila male germ cell differentiation

研究 dUTX 在果蝇雄性生殖细胞分化中的作用

• 批准号: 8586855
• 负责人: Lama Tarayrah
• 金额: $ 4.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-11-16 至 2014-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586855
• 关键词: Adult; Alleles; Bioinformatics; Cancer Biology; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cell Nucleolus; Cell Therapy; Cells; ChIP-seq; Chromatin; Complex; DNA Sequence; Data Analyses; Daughter; Defect; Disease; Drosophila genus; Epigenetic Process; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Germ Cells; Histone H3; Homologous Gene; Human; Immunoblot Analysis; Infertility; Link; Lysine; MLL2 gene; Malignant Neoplasms; Methylation; Methyltransferase; Mitotic; Molecular; Molecular Genetics; Mutation; Nuclear; PRC1 Protein; Pathway interactions; Play; Polycomb; Property; Protein Family; Proteins; Publishing; Recruitment Activity; Regenerative Medicine; Regulation; Reporting; Repression; Research; Role; Signal Transduction; Spermatocytes; Stem cells; System; Testis; Therapeutic; Tissues; Transcript; Transcription Repressor/Corepressor; Tumor Suppressor Proteins; Undifferentiated; X Chromosome; active method; adult stem cell; cell type; chromatin immunoprecipitation; daughter cell; fly; gain of function; genome-wide analysis; histone methyltransferase; human TAF1 protein; human disease; loss of function; male; prevent; programs; promoter; protein complex; regenerative; repaired; research study; self-renewal; stem; stem cell biology; tool; transcriptome sequencing

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.

干细胞具有非对称有丝分裂分裂的显着能力，产生两个不同的子细胞。一个女儿维持干细胞的特性和再生效力，而另一个女儿区分了补充专用细胞类型。成年干细胞区分替代受损组织的能力为人体提供了内部修复系统。但是，控制干细胞如何产生终末分化的细胞的确切机制并不是很好的理解。解码有关干细胞维持和分化的分子机制对于进步再生医学和开发基于干细胞的疗法以治疗癌症和组织营养不良等疾病的疗法有很大的希望。 Polycomb组（PCG）是一种蛋白质家族，通过其能够产生抑制性表观遗传标记的能力 - 赖氨酸27（H3K27me3）的组蛋白H3甲基化的能力。该标记由Polycomb抑制复合物2（PRC2）奠定，而新兴的情况是PRC2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需的。在果蝇雄性种系干细胞谱系中，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）的睾丸特异性同源物的表达水平平行增加，而H3K27ME3水平降低了术语分化基因的H3K27ME3水平。 X染色体上哺乳动物普遍转录的四肽基因（DUTX）的果蝇同源物是唯一的H3K27me3脱甲基酶。它作为抑制性商标的橡皮擦和PCG蛋白的拮抗剂的功能表明，杜克斯在调节从增殖到分化的过渡中起作用。此外，最近已显示出哺乳动物UTX与TRX的哺乳动物同源物H3K4ME3组蛋白甲基转移酶MLL2相关，这增加了DUTX和TRXG蛋白以及TTAF之间相互作用的可能性。对H3K27me3水平的牢固控制对于维持对扩散到分化过渡的严格调节是必要的。灭活UTX的突变与人类癌症有关。因此，DUTX在PCG沉默逆转中的潜在作用使其成为癌症治疗剂的有希望的目标。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。