The Role of Epigenetic Factors in Regulation of Coding and Non-Coding HOX Genes

拒绝3.表观遗传因子在编码和非编码HOX基因调控中的作用。 发育过程中基因表达的表观遗传调控依赖于两个大基因的产物 amilies，三胸组（trxG）的激活剂和Polycomb组（PcG）的阻遏物。的 它们的功能的新图像表明，这些蛋白质通过改变蛋白质的结构来发挥它们的活性。 染色质结构的靶基因。重要的是，不管trxG和PcG如何表达， 蛋白质发挥其活性，它们能够锁定基因表达的特定状态， 然后在子细胞中以表观遗传的方式遗传。对这两组蛋白质的研究 具有重要的健康相关应用，因为这些蛋白质中的一些，例如ALL-1/MLL， 被认为与许多癌症有关。我们的数据表明trxG蛋白复合物 TAC 1含有ALL-1的果蝇同源物，是细胞凋亡网络的重要组成部分。 促进RNA聚合酶II（Pol II）延伸的因子。招募TAC 1加入延长期 3 ol II依赖于许多延伸因子，并伴随着组蛋白的修饰， 其靶同源异型基因超双胸（Ubx）的编码区。我们还发现TAG 1是 对于许多非编码基因间转录物（ncRNA）的转录延伸至关重要， Ubx基因座。这些ncRNA的表达先于Ubx的表达并抑制Ubx 在发育中的胚胎的某些细胞中表达。ncRNA的抑制可能发生在新的 对于高等真核生物的转录干扰机制，虽然其他基于转录的 也不能排除抑制机制。为了将这些研究扩展到BX的其他地区- 并进一步了解TAC 1与其他trxG和PcG蛋白的结合功能 我们将：（i）研究上游ncRNA抑制Ubx的机制;（ii）扩展这些机制。 研究BX-C中的其他ncRNA和其他HOX基因;（iii）研究TAC 1和 Ubx启动子处的其他trxG蛋白和bxd ncRNA;（iv）研究trxG和PcG的功能 复合体的共同表观遗传因素。这些问题的答案将揭示新的光， 这一发现不仅将揭示TAC 1在转录调控中发挥作用的方式，而且还将揭示TAC 1在转录调控中的作用。 其他trxG和PcG蛋白在细胞周期中的表观遗传维持。令人兴奋的新 TAC 1对HOX基因调控的部分作用可能是通过其对HOX基因的调控来实现的。 ncRNA反过来又是产生HQX基因表达的嵌合模式所必需的。 相关性（参见说明）： 鉴于TRX和ALL-1之间的结构和功能相似性，以及人类HOX 簇也包含ncRNA，这些研究将大大推进我们对基本的 高等真核生物的转录调控机制及其与疾病的相关性， 癌

reject 3. The role of epigenetic factors in regulation of coding and non-coding HOX genes. Epigenetic regulation of gene expression during development relies on the products of two large gene amilies, the trithorax-group (trxG) of activators and the Polycomb-group (PcG) of repressers. The emerging picture of their functioning suggests that these proteins exert their activities by altering the chromatin structure of their target genes. Importantly, irrespective of the ways in which trxG and PcG proteins exert their activities, they are capable of locking in a specific status of gene expression, which s then inherited in an epigenetic fashion in daughter cells. The studies of these two groups of proteins have an important health-related application since some of these proteins, as for example ALL-1/MLL, are believed to be involved in a number of cancers. Our data suggest that the trxG protein complex TAC1, containing a Drosophila homologue of ALL-1, is an essential component of the network of factors that facilitate elongation by RNA polymerase II (Pol II). Recruitment of TAC1 to the elonagting 3ol II depends on a number of elongation factors, and is accompanied by modifications of histones in the coding region of its target homeotic gene Ultrabithorax (Ubx). We also discovered that TAG1 is essential for transcriptional elongation of a number of non-coding intergenic transcripts (ncRNAs) in the Ubx locus. Expression of these ncRNAs precedes expression of Ubx and represses Ubx expression in certain cells of the developing embryo. Repression by ncRNAs may occur by the novel for higher eukaryotes transcription interference mechanism, although other transcription-based repression mechanisms cannot be also excluded. To extend these studies for other regions of the BX- C and to obtain further insight into functioning of TAC1 in conjunction with other trxG and PcG proteins we will: (i) Investigate the mechanisms of Ubx repression by the upstream ncRNAs; (ii) Extend these studies to other ncRNAs and other HOX genes in the BX-C; (iii) Investigatethe roles of TAC1 and other trxG proteins at Ubx promoter and bxd ncRNAs; (iv) Investigate functioning of trxG and PcG complexes at their common epigenetic elements. Answers to these questions will shed new light not only on the way TAC1 exerts its effects during transcriptional regulation, but will also reveal the roles of other trxG and PcG proteins in epigenetic maintenance during cell cycle. The exciting new possibility is that part of the TAC1 effect on HOX gene regulation may occur through its regulation of ncRNAs that in their turn are essential for creating mosaic patterns of HQX gene expression. RELEVANCE (See instructions): Given structural and functional similarities between TRX and ALL-1, and the fact that human HOX clusters also contain ncRNAs, these studies will greatly advance our knowledge of the basic mechanisms of transcriptional regulation in higher eukaryotes and their relevance to diseases like cancer.