Oncotarget

Research Papers: Pathology:

Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants

Carlos Alberto Moreira-Filho _, Silvia Yumi Bando, Fernanda Bernardi Bertonha, Filipi Nascimento Silva, Luciano da Fontoura Costa, Leandro Rodrigues Ferreira, Glaucio Furlanetto, Paulo Chacur, Maria Claudia Nogueira Zerbini and Magda Carneiro-Sampaio

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Oncotarget. 2016; 7:7497-7533. https://doi.org/10.18632/oncotarget.7120

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Abstract

Carlos Alberto Moreira-Filho1, Silvia Yumi Bando2, Fernanda Bernardi Bertonha3, Filipi Nascimento Silva4, Luciano da Fontoura Costa5, Leandro Rodrigues Ferreira6, Glaucio Furlanetto7, Paulo Chacur8, Maria Claudia Nogueira Zerbini9 and Magda Carneiro-Sampaio10

1 Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

2 Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

3 Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

4 Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brasil

5 Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brasil

6 Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

7 Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brasil

8 Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brasil

9 Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

10 Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Correspondence to:

Carlos Alberto Moreira-Filho, email:

Keywords: thymus, Down syndrome, gene coexpression network, modular transcriptional repertoire, microRNA, Pathology Section

Received: October 02, 2015 Accepted: January 23, 2016 Published: February 01, 2016

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.


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