Background
Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease driven by both environmental and genetic factors. Epigenetics refers to changes in gene expression or cellular phenotype that do not involve alterations to DNA sequence. KMT2A is a member of the SET family which catalyses H3K4 methylation.
Conclusion
The current study indicated that histone modification participates in the pathogenesis of IPF and KMT2A may have the potential to be a therapeutic target of IPF treatment. Key points: KMT2A plays a role in pulmonary fibrogenesis. KMT2A regulates PU.1 transcription in fibroblasts through H3K4me3 at promoter. KMT2A inhibitor attenuates pulmonary fibrosis in mice.
Results
Through microarray and single-cell sequencing data, we discovered KMT2A-positive fibroblasts were increased in IPF lung tissues. KMT2A level was increased in IPF and bleomycin-induced pulmonary fibrosis mice lung tissues collected in our centre. Mice with AAV6-induced KMT2A knockdown in fibroblast showed attenuated pulmonary fibrosis after bleomycin treatment. Bioinformation also revealed that transcription factor PU.1 was a target of KMT2A. We demonstrated that PU.1 levels were increased in IPF tissues, bleomycin-induced mice lung tissues and primary fibrotic fibroblasts. KMT2A knockdown decreases PU.1 expression in vitro while KMT2A overexpression induces PU.1 activation. PU.1 fibroblast-specific knockout mice showed attenuated lung fibrosis induced by bleomycin. Furthermore, we demonstrated KMT2A up-regulated PU.1 in fibroblasts by catalysing H3K4me3 at the promoter of the PU.1 gene. The KMT2A transcription complex inhibitor mm102 treatment attenuated bleomycin-induced pulmonary fibrosis.