title: MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. The understanding of its gene expression regulation and molecular mechanisms still remains elusive. Started from experimentally verified T-ALL-related miRNAs and genes, we obtained 120 feed-forward loops (FFLs) among T-ALL-related genes, miRNAs and TFs through combining target prediction. 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 four 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 represses CYLD expression, while miR-19 inhibitor treatment induces CYLD protein expression and decreases NF-κB expression in the downstream signaling pathway. Thus, miR-19, CYLD and NF-κB form a regulatory FFL, which provides new clues for sustained activation of NF-κB in T-ALL. Taken together, we provided the first miRNA-TF co-regulatory network in T-ALL and proposed a model to demonstrate the roles of miR-19 and CYLD in the T-cell leukemogenesis. This study may provide potential therapeutic targets for T-ALL and shed light on combining bioinformatics with experiments in the research of complex diseases.
authors.affiliation: Hubei Bioinformatics and Molecular Imaging Key Laboratory, Department of Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Huashan
authors.initials: H
authors.lastname: Ye
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Lv
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Wu
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Kuang
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.forename: Zhaodong
authors.initials: Z
authors.lastname: Zhong
authors.forename: Qiubai
authors.initials: Q
authors.lastname: Li
authors.forename: Haibo
authors.initials: H
authors.lastname: Jia
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Chen
authors.forename: An-Yuan
authors.initials: AY
authors.lastname: Guo
mesh_terms: D045744:Cell Line, Tumor; D000074749:Deubiquitinating Enzyme CYLD; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD