Uncovering the Epigenetic Contribution of Protein Arginine Methyltransferase 5 (PRMT5) during Zebrafish Cardiomyogenesis

Abstract

The heart develops through an extremely intricate process mediated by a network of transcription factors initiated by key chromatin modification events. Scientist have implicated the protein arginine methyltransferase 5 (PRMT5) in the regulation of cell specific gene expression programs. In turn, this drives the correct proliferation and differentiation of different types of cells. We showed her that the knockdown of morpholino antisense oligonucleotide-mediated PRMT5 in zebrafish embryos delays heart development. This was accompanied by a moderate decrease in blood flow (20%), significantly higher decrease in general cardiac output (65%), and reduction in red blood cells count (50%). The reduction of the expression of PRMT5 also resulted in a 4-fold decrease in the rate of hatching and had negative impacts on locomotion and tail flicking in PRMT5 morphants. Conversely, these phenotypes were almost fully rescued by the re-expression of human PRMT5. The expression of transcription factors (GATA5, MYF5, and CDC37) which are required in the initial stages of cardiomyogenesis was investigated. As well as the key heart failure markers, ANP/NPPA and BNP/NPPB. The knockdown of PRMT5 resulted in a decline in transcription of all the target genes studies 24 and 48 hpf. However, there were restorations or slight increases in the ANP/NPPA and BNP/NPPB mRNAs levels 72hpf relative to the control embryos. Analysis of chromatin immunoprecipitation (ChIP) showed that the promoter region of GATA5 and MYF5 are directly targeted by PRMT5, which are both are required for cardiomyocyte differentiation. From these results, it is inferred that PRMT5 is necessary for the normal heart development in zebrafish. This is because the characteristics of PRMT5 regulate the expression of key cardiac transcription factors