Histone methyltransferase KMT2A promotes pulmonary fibrogenesis via targeting pro-fibrotic factor PU.1 in fibroblasts

Abstract

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.

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.

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.