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第五届全国生物信息学与系统生物学学术大会暨国际生物信息学前沿研讨会高通量时代的生物信息学与系统生物学

作者： Xuerui Yang Pavel Sumazin Wei-Jen Chung Hua-Sheng Chiu andrea califano Center for Computational Biology and Bioinformatics Columbia Initiative in Systems Biology Columbia University

Background:microRNAs(miRs) have emerged as key regulators of both normal and pathologic phenotypes,including *** activities and biogenesis of miRs are heavily *** of physiologic miR activity and biogenesis has been shown to play an important role in tumor initiation and ***,few modulators of miR activity and biogenesis have been characterized,and both the extent and relevance of their role in controlling normal cell physiology and pathogenesis are poorly understood. Methods:Systematic approaches were exploited to dissect microRNA-related post- transcriptional regulatory networks that are associated with human ***,by analyzing mRNA and miR expression profiles of a large set of glioblastoma patient samples, miR activity and biogenesis regulations have been studied in a genome-wide scale. Results:First,genome-wide screening of miR activity regulators uncovered a previously-uncharacterized layer of post-transcriptional regulation,involving 7,000 RNAs that act as miR "sponges" and participate in more than 248,000 miR program-mediated (mPM) *** regulation layer also includes 148 genes that regulate individual miR activity on its targets through alternative,nonsponge *** mPM interactions as a network mediate crosstalk between canonical oncogenic pathways and connect genetically distant genes,which was experimentally validated in tumor cell *** mPM interactions also provide mechanistic rationales for regulation of key genes in cancer,and largely explain missing genetic variations in various patient *** interaction networks were also reconstructed for breast,prostate,and ovarian ***,hundreds of novel regulators of miR biogenesis were discovered through a genome-wide screening using the same dataset as above.A subset of these regulators have been experimentally validated via high-,mid-,and low-throughput profiling of primary,precursor,and mature miRs in additio

关键词： microRNA activity biogenesis sponge regulation post-transcriptional

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肿瘤恶性转化与C/EBPβ和STAT3基因相关(英文)

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中华神经外科疾病研究杂志 2010年第1期9卷 22-22页

作者： Maria Stella Carro Wei Keat Lim Mariano Javier Alvarez Robert J. Bollo Evan Y. Snyder Erik P. Sulman Sandrine L. Anne Fiona Doetsch Howard Colman Anna Lasorella Ken Aldape andrea califano Antonio Iavarone

The inference of transcriptional networks that regulate transitions into physiological or pathological cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumour aggressiveness in human malignant glioma,but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here we show that reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage,whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumour aggressiveness. In human glioma,expression of C/EBPβ and STAT3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results show that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.

关键词：脑瘤细胞分子生理学临床分析

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