Histone arginine methylation by Prmt5 is required for lung branching morphogenesis through repression of BMP signaling

Branching morphogenesis is essential for the successful development of a functional lung to accomplish its gas exchange function. Although many studies have highlighted requirements for the bone morphogenetic protein (BMP) signaling pathway during branching morphogenesis, little is known about how BMP signalingis regulated. Here we report that the protein arginine methyltransferase 5 (Prmt5) and symmetric dimethylation at histone H4 arginine 3 (H4R3sme2) directly associate with chromatin of Bmp4 to suppress its transcription. Inactivation of Prmt5 in the lung epithelium results in halted branching morphogenesis, altered epithelial cell differentiation and neonatal lethality. These defects are accompanied by increased apoptosis and reduced proliferation of lung epithelium, as a consequence of elevated canonical BMP-Smad1/5/9 signaling. Inhibition of BMP signaling by Noggin rescues the lung branching defects of Prmt5 mutant in vitro. Taken together, our results identify a novel mechanism through which Prmt5-mediated histone arginine methylation represses canonical BMP signaling to regulate lung branching morphogenesis. In order to further explore the molecular mechanism of cell deletion in ciliated cells after Prmt5 knockout in epithelial cells,We chose the E13.5 period and put Shh; Prmt5 embryo and litter control of the main airway part (including trachea and lung Isolated from the whole lung, RNA was extracted for transcriptome sequencing (RNA-SEQ) analysis.