FIGURE 3

Combination of RNA‐seq with an F0‐based genetic screen identified fabp7a as a therapeutic modifier gene for the bag3 cardiomyopathy model. (A, B) Principal Component Analysis (PCA) of RNA‐seq‐based expression data from the mtor^xu015/+ mutant (A) or Tg(cmlc2:tfeb) (B) transgenic fish hearts compared to WT controls. (C) 3D PCA plot using the normalized gene expression of all expressed genes to assess the genome‐wide transcriptomic similarity among mtor^xu015/+ mutant, Tg(cmlc2:tfeb) transgenic fish hearts, and WT controls. (D) Comparison of cardiac transcriptome between mtor^xu015/+ mutant and Tg(cmlc2:tfeb) transgenic fish hearts identified 10 upregulated and 15 downregulated genes as common DEGs. (E) Quantitative RT‐PCR validated the expression of 4 lipodystrophic DE genes that were downregulated in both the mtor^xu015/+ mutant and the Tg(cmlc2:tfeb) transgenic hearts. (F) List of single guide RNA (sgRNA) sequences for the 4 lipodystrophic DE genes and knockout scores detected from the adult fish injected with sgRNAs in F0 generation. (G) Injection of fabp7a microhomology‐mediated end joining (MMEJ)‐inducing sgRNA, but not the other 3 individual MMEJ sgRNAs, exerts a cardioprotective effect on bag3^e2/e2 cardiomyopathy in F0 adult fish.