TRISOMY 21-DRIVEN GENE EXPRESSION DYSREGULATION IN HUMAN THYMUS: CONVERGING GENOMIC AND EPIGENOMIC MECHANISMS

Saturday, April 16, 2016
Commonwealth Hall ABC (Seaport Hotel)
Magda Carneiro-Sampaio, MD, PhD (Universidade de Sao Paulo)
Trisomy 21-driven genomic dysregulation on human thymus was assessed by topological analyses of gene coexpression networks (GCNs) - obtained for differential expressed genes (DE networks), and for the global gene expression (CO networks) - in thymic tissue of Down syndrome (DS) and karyotipically normal subjects (CS). These data were integrated with miRNA target analysis in order to investigate the mechanism by which trisomy 21 alters the canonical thymic transcriptional program. The integration of community structure (modular transcriptional repertoire) and miRNA target analyses allowed the identification of the leading GCNs that correspond to thymus functioning in CS and DS subjects. DE networks are subnetworks of CO networks and the comparative analysis of DS-DE and CS-DE networks portrays the “ground zero”: the subnetwork transition considering only the genes whose transcription was significantly altered by trisomy 21. Conversely, the comparative analysis of DS-CO and CS-CO networks reveals the derived “shock-waves” of trisomy 21 genomic dysregulation, reflecting its effects on the organ’s global transcriptional program. Finally, most of the highly connected genes in DS and CS networks were under tight miRNA control – including abundantly expressed miRNAs - thus indicating that epigenetic mechanisms are involved in the thymic adaptation to trisomy 21 dysregulation.