title: Comprehensive Survey of miRNA-mRNA Interactions Reveals That Ccr7 and Cd247 (CD3 zeta) are Posttranscriptionally Controlled in Pancreas Infiltrating T Lymphocytes of Non-Obese Diabetic (NOD) Mice.
abstract: In autoimmune type 1 diabetes mellitus (T1D), auto-reactive clones of CD4+ and CD8+ T lymphocytes in the periphery evolve into pancreas-infiltrating T lymphocytes (PILs), which destroy insulin-producing beta-cells through inflammatory insulitis. Previously, we demonstrated that, during the development of T1D in non-obese diabetic (NOD) mice, a set of immune/inflammatory reactivity genes were differentially expressed in T lymphocytes. However, the posttranscriptional control involving miRNA interactions that occur during the evolution of thymocytes into PILs remains unknown. In this study, we postulated that miRNAs are differentially expressed during this period and that these miRNAs can interact with mRNAs involved in auto-reactivity during the progression of insulitis. To test this hypothesis, we used NOD mice to perform, for the first time, a comprehensive survey of miRNA and mRNA expression as thymocytes mature into peripheral CD3+ T lymphocytes and, subsequently, into PILs. Reconstruction of miRNA-mRNA interaction networks for target prediction revealed the participation of a large set of miRNAs that regulate mRNA targets related to apoptosis, cell adhesion, cellular regulation, cellular component organization, cellular processes, development and the immune system, among others. The interactions between miR-202-3p and the Ccr7 chemokine receptor mRNA or Cd247 (Cd3 zeta chain) mRNA found in PILs are highlighted because these interactions can contribute to a better understanding of how the lack of immune homeostasis and the emergence of autoimmunity (e.g., T1D) can be associated with the decreased activity of Ccr7 or Cd247, as previously observed in NOD mice. We demonstrate that these mRNAs are controlled at the posttranscriptional level in PILs.
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Thais A
authors.initials: TA
authors.lastname: Fornari
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Donate
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Assis
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Claudia
authors.initials: C
authors.lastname: Macedo
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), 14049-900, Ribeirão Preto, SP, Brazil.|Department of Biology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, USP, 14040-900, Ribeirão Preto, SP, Brazil.
authors.forename: Elza T
authors.initials: ET
authors.lastname: Sakamoto-Hojo
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), 14049-900, Ribeirão Preto, SP, Brazil.|Department of Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, USP, 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Donadi
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), 14049-900, Ribeirão Preto, SP, Brazil.|Department of Morphology, Physiology and Basic Pathology, Disciplines of Genetics and Molecular Biology, School of Dentistry of Ribeirão Preto, USP, 14040-904, Ribeirão Preto, SP, Brazil.
authors.forename: Geraldo A
authors.initials: GA
authors.lastname: Passos
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D017252:CD3 Complex / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D017930:Genes, Reporter; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000235:genetics*; D010179:Pancreas / Q000276:immunology / Q000378:metabolism*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics*; D054400:Receptors, CCR7 / Q000235:genetics*; D015203:Reproducibility of Results; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome
chemical_list: D020413:3' Untranslated Regions; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D035683:MicroRNAs; D012333:RNA, Messenger; D054400:Receptors, CCR7