title: Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants.
abstract: Trisomy 21-driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and miRNA-target analyses. We used whole thymic tissue--obtained at heart surgery from Down syndrome (DS) and karyotipically normal subjects (CT)--and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires (communities) and the interactions between all the system's constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS networks corresponded to community changes. Distinct communities of highly interconnected genes were topologically identified in these networks. The role of miRNAs in modulating the expression of highly connected genes in CT and DS was revealed through miRNA-target analysis. Trisomy 21 gene dysregulation in thymus may be depicted as the breakdown and altered reorganization of transcriptional modules. Leading networks acting in normal or disease states were identified. CT networks would depict the "canonical" way of thymus functioning. Conversely, DS networks represent a "non-canonical" way, i.e., thymic tissue adaptation under trisomy 21 genomic dysregulation. This adaptation is probably driven by epigenetic mechanisms acting at chromatin level and through the miRNA control of transcriptional programs involving the networks' high-hierarchy genes.
authors: Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
authors: Carlos Alberto
authors: CA
authors: Moreira-Filho
authors: Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
authors: Silvia Yumi
authors: SY
authors: Bando
authors: Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
authors: Fernanda Bernardi
authors: FB
authors: Bertonha
authors: Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brasil.
authors: Filipi Nascimento
authors: FN
authors: Silva
authors: Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brasil.
authors: Luciano da Fontoura
authors: Lda F
authors: Costa
authors: Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
authors: Leandro Rodrigues
authors: LR
authors: Ferreira
authors: Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brasil.
authors: Glaucio
authors: G
authors: Furlanetto
authors: Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brasil.
authors: Paulo
authors: P
authors: Chacur
authors: Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
authors: Maria Claudia Nogueira
authors: MC
authors: Zerbini
authors: Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
authors: Magda
authors: M
authors: Carneiro-Sampaio
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D004314:Down Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger
keywords: Down syndrome; Pathology Section; gene coexpression network; microRNA; modular transcriptional repertoire; thymus