Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy
Fig 8
Hypertrabeculated Nkx2-5 mutant hearts suffered transcriptional changes in developmental, functional and inflammatory processes.
(A) 2D Hierarchical clustering of differentially expressed genes (Significance Analysis of Microarrays (SAM) 3 classes, 10,000 permutations, FDR < 0,05, TMeV) shows clearly the 3 differentiate groups corresponding to Control, Nkx2-5ΔTrbE10 and Nkx2-5ΔTrbE14 6 month-old mutant mice (N = 4 per group). Enriched Biological Process (BP)-GO terms for the 7 clusters are indicated and representative genes (selected for their role in cardiomyopathies or described in Nkx2-5 mutants) are noted. (B) Venn diagrams show the number of genes significantly up- and down-regulated in Nkx2-5ΔTrbE10 and Nkx2-5ΔTrbE14 mutants vs control mice (SAM 2 classes, FDR < 0.05, TMeV). Note that specifically up-regulated genes are twice numerous than the down-regulated genes and that the number of genes deregulated in Nkx2-5ΔTrbE10 mutant is much greater than in Nkx2-5ΔTrbE14 mutant (592 vs 344). A gene ontology analysis realized with David Database is reported on the graph in which the most significant representative BP are indicated. For all processes, the number of genes deregulated in Nkx2-5ΔTrbE10 mutant is much greater than in Nkx2-5ΔTrbE14 mutant. (C) Gene network diagram carried out with venn diagram genes whose fold change is ≥ 2. Blue rectangles correspond to the most significant BP found in Nkx2-5ΔTrbE10 mutant and green rectangles, BP found in Nkx2-5ΔTrbE14 mutant. A vast majority of the most significant BP were jointly found in both mutants and are colored in blue/green (David Database, P-Benjamini <0.05). Genes implicated in these pathways are indicated in blue when they are specific for Nkx2-5ΔTrbE10, in green for Nkx2-5ΔTrbE14 mutant and in black when they are common. Red circles indicate genes validated by qPCR.