RESUMO
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.
Assuntos
Biomarcadores/análise , Síndrome de Down/genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genômica/métodos , MicroRNAs/genética , Timo/metabolismo , Síndrome de Down/imunologia , Síndrome de Down/patologia , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Masculino , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Timo/imunologia , Timo/patologiaRESUMO
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 forGCN analysis that allows the identification of modular transcriptional repertoires(communities) and the interactions between all the systems 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 inthese 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 genedys regulation 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 probablydriven by epigenetic mechanisms acting at chromatin level and through the miRNAcontrol of transcriptional programs involving the networks high-hierarchy genes...
