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

拒绝3.表观遗传因素在编码和非编码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、激活剂的三胸基团(TrxG)和阻滞剂的聚梳基(PcG)。这个 新出现的它们的功能图景表明，这些蛋白质通过改变 其靶基因的染色质结构。重要的是，无论trxG和PcG以何种方式 蛋白质发挥其活性，它们能够锁定特定的基因表达状态，这 S随后在子代细胞中以表观遗传方式遗传。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， 被认为与多种癌症有关。我们的数据表明trxG蛋白复合体 Tac1包含果蝇ALL-1的同源物，是 促进RNA聚合酶II(POL II)伸长的因素。招聘Tac1到Elonagting 3ol II依赖于许多伸长因子，并伴随着组蛋白在 同源异型基因Ubx的编码区。我们还发现TAG1是 对一些非编码基因间转录本(NcRNAs)的转录延长是必不可少的 Ubx轨迹。这些ncRNA的表达先于Ubx的表达，并抑制Ubx的表达 在发育中的胚胎的某些细胞中表达。NcRNAs的抑制可能通过小说发生 对于高等真核生物的转录干扰机制，虽然其他以转录为基础 压制机制也不能排除在外。为了将这些研究扩展到不列颠哥伦比亚省的其他地区- C，并进一步了解Tac1与其他trxG和PcG蛋白的功能。 我们将：(I)研究上游ncRNA抑制Ubx的机制；(Ii)扩展这些机制 对BX-C中其他ncRNAs和其他Hox基因的研究；(Iii)研究Tac1和Tac1的作用 Ubx启动子和BxD ncRNAs上的其他trxG蛋白；(Iv)研究trxG和PcG的功能 它们共同的表观遗传元素的复合体。这些问题的答案将为我们带来新的曙光 Tac1不仅在转录调控过程中发挥作用，而且还将揭示其作用 其他trxG和PcG蛋白在细胞周期的表观遗传维持中的作用。激动人心的新消息 可能的是，Tac1对HOX基因调控的部分作用可能是通过其对 NcRNAs反过来对于创造HQX基因表达的镶嵌模式是必不可少的。 相关性(请参阅说明)： 鉴于Trx和ALL-1在结构和功能上的相似性，以及人类Hox 簇中也含有ncRNA，这些研究将极大地推进我们对基础 高等真核生物转录调控机制及其与疾病的关系 癌症。

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.