近日,，國(guó)際著名腫瘤學(xué)雜志Cancer Research發(fā)表了同濟(jì)大學(xué)生命科學(xué)院劉小樂研究組關(guān)于核受體研究的最新成果“A Comprehensive View of Nuclear Receptor Cancer Cistromes”。該研究成果建立了一個(gè)新的模型預(yù)測(cè)轉(zhuǎn)錄因子直接調(diào)控的基因,。
核受體是一類由配體激活的轉(zhuǎn)錄因子，在正常生理和如癌癥的疾病中都扮演重要角色,。通過整合和分析現(xiàn)有的核受體ChIP-chip/seq數(shù)據(jù),，該工作揭示了有關(guān)核受體調(diào)控機(jī)理的一些有意義現(xiàn)象：核受體識(shí)別的非典型模體，于其共同作用的先導(dǎo)因子特點(diǎn),，其結(jié)合位點(diǎn)的強(qiáng)度／保守性和功能性的關(guān)系,，及其在轉(zhuǎn)錄調(diào)控中的作用,。該工作通過整合同一細(xì)胞株和條件下同一轉(zhuǎn)錄因子的全部ChIP-chip/seq數(shù)據(jù)和與之匹配的全部差異表達(dá)數(shù)據(jù)，建立了一個(gè)新的模型預(yù)測(cè)轉(zhuǎn)錄因子直接調(diào)控的基因,。該工作提出了不同類型高通量數(shù)據(jù)整合研究轉(zhuǎn)錄調(diào)控機(jī)制的新思路,。
本研究工作是在劉小樂教授的指導(dǎo)下，主要由同濟(jì)大學(xué)生命科學(xué)院博士研究生唐茜子完成,。劉小樂教授是哈佛大學(xué)公共衛(wèi)生學(xué)院生物統(tǒng)計(jì)系的副教授,，同濟(jì)大學(xué)生命科學(xué)與技術(shù)學(xué)院兼職教授，博士生導(dǎo)師,。該研究工作得到了科技部的經(jīng)費(fèi)支持,。(生物谷Bioon.com)
doi:10.1158/0008-5472.CAN-11-2091
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A Comprehensive View of Nuclear Receptor Cancer Cistromes
Qianzi Tang Yiwen Chen Clifford Meyer Tim Geistlinger Mathieu Lupien Qian Wang Tao Liu Yong Zhang Myles Brownand and Xiaole Shirley Liu
Nuclear receptors (NRs) comprise a superfamily of ligand-activated transcription factors that play important roles in both physiology and diseases including cancer. The technologies of Chromatin ImmunoPrecipitation followed by array hybridization (ChIP-chip) or massively parallel sequencing (ChIP-seq) has been used to map, at an unprecedented rate, the in vivo genome-wide binding (cistrome) of NRs in both normal and cancer cells. We developed a curated database of 88 NR cistrome datasets and other associated high-throughput datasets, including 121 collaborating factor cistromes, 94 epigenomes and 319 transcriptomes. Through integrative analysis of the curated NR ChIP-chip/seq datasets, we discovered novel factor-specific noncanonical motifs that may have important regulatory roles. We also revealed a common feature of NR pioneering factors to recognize relatively short and AT-rich motifs. Most NRs bind predominantly to introns and distal intergenetic regions, and binding sites closer to transcription start sites (TSSs) were found to be neither stronger nor more evolutionarily conserved. Interestingly, while most NRs appear to be predominantly transcriptional activators, our analysis suggests that the binding of ESR1, RARA and RARG has both activating and repressive effects. Through meta-analysis of different omic data of the same cancer cell line model from multiple studies, we generated consensus cistrome and expression profiles. We further made probabilistic predictions of the NR target genes by integrating cistrome and transcriptome data, and validated the predictions using expression data from tumor samples. The final database, with comprehensive cistrome, epigenome, transcriptome datasets, and downstream analysis results, constitutes a valuable resource for the nuclear receptor and cancer community.
