miR-17-92基因簇在细胞衰老过程中的转录调控机制

microRNAs are recently discovered class of small non-coding RNA species that regulate gene expression at the post-transcriptional level. microRNAs that represented a novel regulatory mechanism in gene expression play fundamental roles in a broad spectrum of biological activities, including development, differentiation, cell death and oncogenesis. miR-17-92 cluster was the first microRNA cluster identified with oncogenic potential and was therefore termed as oncomir-1, which frequently altered or dysregulated in various human cancers. .We have previously identified two members of the miR-17-92 cluster microRNAs miR-17-5p and miR-20a down-regulated in senescent cells. We further showed that miR-17-5p and miR-20a involved in the cellular senescence by targeting the cell cycle regulator E2F1. Recent studies demonstrated that the members of miR-17-92 cluster miR-17-5p, miR-19b and miR-20a are down regulated in human aging including four cell types of cellular senescence model and three human aging tissues, suggesting that miR-17-92 cluster play important roles in cellular and organismal aging..By using bioinformatics and chip-seq experimental database analysis, we found that the promoter region of miR-17-92 cluster has a large CpG island, multiple H3K4me3, H3K9Ac sites and conserved transcription factor binding sites, indicating the transcriptional regulation of miR-17-92 cluster expression. This project aims to study the transcriptional regulation of the miR-17-92 cluster during cellular senescence and to establish regulatory network between miR-17-92 cluster, its target genes and the transcriptional factors that controlling the miR-17-92 cluster transcription.

microRNA是一类进化上保守的非编码RNA，在转录后水平抑制蛋白编码基因的表达。microRNA代表一个新层次上的基因表达调控方式，通过调控基因表达参与发育、分化、衰老及癌变等许多重要生物学过程。miR-17-92基因簇是第一个被鉴定的具有癌基因作用的microRNA基因簇，命名为oncomir-1，在多种肿瘤组织中过表达。.我们前期工作发现miR-17-92基因簇的成员miR-17-5p和miR-20a在细胞衰老过程中表达显著下调，并证明miR-17-5p和miR-20a通过抑制E2F1基因表达参与细胞衰老的调节。有报道显示miR-17-92基因簇中的miR-17-5p，miR-19b和miR-20a在人的四种细胞衰老模型和三种组织衰老模型中表达显著下调，说明miR-17-92基因簇在细胞和组织衰老中起重要作用。本项目拟研究miR-17-92基因簇在细胞衰老过程中转录调节机制。

microRNA 是一类进化上保守的非编码RNA (ncRNAs)，通常在转录后水平抑制蛋白编码基因的表达。microRNA 代表一个新层次上的基因表达调控方式，通过调控基因表达参与发育、分化、衰老及癌变等许多重要生物学过程。miR-17-92 基因簇是第一个被鉴定的具有癌基因作用的microRNA 基因簇，命名为oncomir-1，在多种肿瘤组织中过表达。miR-17-92基因簇通过促进细胞增殖，抑制分化，促进血管生成以及维持细胞生存等同时参与正常的生物体发育和肿瘤恶性转变过程。miR-17-92基因簇包含miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1和miR-92a-1等6个miRNA成员，这些成员作为一个多顺反子共同转录，每一个miRNA都可能会调节成百上千的靶基因。这种特殊的基因结构可能作为一种分子基础决定了miR-17-92基因簇的作用具有细胞和组织特异性。.本实验室发现miR-17-92 基因簇的成员miR-17-5p 和miR-20a 在细胞衰老过程中表达显著下调，并证明miR-17-5p 和miR-20a可以通过抑制E2F1 基因表达而抑制细胞的衰老，说明miR-17-92 基因簇在细胞衰老中起重要作用。miR-17-92基因簇在衰老过程中的表达如何受到调控尚不清楚。依据生物信息学分析和数据库收录的ChIP-Seq实验结果，我们发现在miR-17 前体序列上游4.2kb 到下游1kb（-4.2kb 到1kb）之间存在大的甲基化岛和多个在进化上保守的转录因子结合位点，因此我们预测这段序列可能是miR-17-92 基因簇的转录调控区域，在miR-17-92 基因簇的转录调控中起重要作用。本项目主要从表观遗传机制和转录因子调控基因转录两个方面探讨miR-17-92基因簇在细胞衰老过程中的调控。