转录因子和miRNA在复杂疾病中的共调控网络研究
Transcription factors (TFs) are key regulators controlling the transcription of target genes by binding to specific DNA sequences on the promoter of target genes. Both the TFs and miRNAs are regulators of gene expression and they may mutual regulate each other to form feedback loops (FBL), or they regulate the same target gene to form a feed-forward loop (FFL). It has been reported that hundreds of potential miRNA-mediated feedback and feed-forward loops are available at the genome level. To predict the TF-miRNA co-regulatory FFL and FBL loops, we integrated multiple data of TF targets and miRNA targets including both experimentally validated and predicted. Thus, we developed a strategy to predict the TF-miRNA co-regulatory FFL and FBL loops. We used these methods to study the TF-miRNA co-regulation in specific diseases including schizophrenia and T-cell acute lymphoblastic leukemia (T-ALL). We identified and verified some key miRNA and genes in these diseases. In the T-ALL, we obtained 120 FFLs among T-ALL related genes, miRNAs and TFs. Afterwards, a T-ALL miRNA and TF co-regulatory network was constructed and its significance was tested by statistical methods. Four miRNAs in the miR-17~92 cluster and 4 important genes (CYLD, HOXA9, BCL2L11, and RUNX1) were found as hubs in the network. Particularly, we found that miR-19 was highly expressed in T-ALL patients and cell lines. Ectopic expression of miR-19 repress CYLD expression, while miR-19 inhibitor treatment induce CYLD protein expression and decreases NF-κB expression in the downstream signaling pathway. Thus, miR-19, CYLD and NF-κB form a regulatory feed-forward loop, which provides new clues for sustained activation of NF-κB in T-ALL. Some single nucleotide polymorphisms (SNPs) in miRNA genes or target sites (miRNA-related SNPs) have been proved to be associated with human diseases by affecting the miRNA mediated regulatory function. To systematically analyze miRNA-related SNPs and their effects, we performed a genome-wide scan for SNPs in human pre-miRNAs, miRNA flanking regions, target sites and designed a pipeline to predict the effects of them on miRNA-target interaction. As a result, we identified 48 SNPs in human miRNA seed regions and thousands of SNPs in 3'- untranslated regions with the potential to either disturb or create miRNA-target interactions. Furthermore, we experimentally confirmed 7 loss-of-function SNPs and 1 gain-of-function SNP by luciferase assay. All useful data were complied into miRNASNP, a user-friendly free online database (http://www.bioguo.org/miRNASNP/). These data will be a useful resource for studying miRNA function, identifying disease-associated miRNAs, and further personalized medicine.
转录因子和miRNA在复杂疾病中的共调控网络研究
Transcription factors (TFs) are key regulators controlling the transcription of target genes by binding to specific DNA sequences on the promoter of target genes. Both the TFs and miRNAs are regulators of gene expression and they may mutual regulate each other to form feedback loops (FBL), or they regulate the same target gene to form a feed-forward loop (FFL). It has been reported that hundreds of potential miRNA-mediated feedback and feed-forward loops are available at the genome level.
干细胞中的长链非编码RNA功能与RNA调控网络研究
近年来大量研究表明非编码RNA在人类疾病的调控中扮演了越来越重要的角色。包括肿瘤、神经系统疾病、心血管病的发生、以及参与免疫与代谢疾病调控、精子发育调控等，为开发疾病诊断标志物以及筛选新药靶标带来诸多新的方向。本次网络研讨会将围绕非编码RNA调控机理， 技术方法以及与疾病关系邀请名专家学者座谈，分享最新非编码RNA研究成果与经验，推动学科发展，促进转化医学及合作。