The histone methyltransferase DOT1L is a new epigenetic regulator of pulmonary fibrosis

Di Yang,Peng Xu,Xinhua Liu,Jie Xu,Haibi Su,Wen Zhong,Zhenghua Su

doi:10.1038/s41419-021-04365-5

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with increasing occurrence, high death rates, and unfavorable treatment regimens. The pathogenesis underlying IPF is complex and the epigenetic contributions to IPF are largely unknown. Recent studies have shown that DOT1L (Disruptor of telomeric silencing-1 like), a histone H3K79 methyltransferase, contributes to fibrosis response, but its role in IPF remains unclear. DOT1L, H3K79me3, and the profibrotic proteins levels were upregulated in the pulmonary fibrosis models both in vivo and in vitro. Lentivirus-mediated DOT1L knockdown or DOT1L-specific inhibitor EPZ5676 alleviated the pathogenesis of bleomycin-induced mouse pulmonary fibrosis. Furthermore, heterozygous DOT1L-deficient mice (Dot1l+/−) showed less sensitive to pulmonary fibrosis, as shown by decreased lung fibrosis phenotypes in vivo. Mechanically, DOT1L regulated TGF-β1-induced fibroblasts fibrosis by increasing enrichments of H3K79me3 on the promoter of Jag1 gene (encoding the Notch ligand Jagged1), enhancing the expression of Jagged1, which in turn stimulated exuberant Notch signaling and actuated the fibrosis response. In conclusion, our study confirmed DOT1L to be an epigenetic modifier in the pathogenesis of lung fibrosis, revealed a counterbalancing mechanism governing Jag1 transcription by modulating H3K79 trimethylation at the Jag1 promoter, activating the Notch signaling, and affecting the expression of profibrotic proteins to accelerate the lung fibrosis.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal fibrotic disease of the lung, characterized by extreme deposition of extracellular matrix (ECM) and destruction of the normal lung architecture [1]
Pulmonary fibrosis is derived by initially repeated epithelial cell damage and subsequently progressive lung scarring that results in the formation of fibroblast and myofibroblast foci [7]
The increased expression of Jag1 mRNA upon TGF-β1 treatment was inhibited by EPZ5676 (Fig. 7G). These findings described above suggest that TGF-β1-induced Disruptor of telomeric silencing 1-like (DOT1L) upregulation might lead to increase the abundance of H3K79 trimethylation at the promoter region of Jag1, promoting Jag1 gene transcription and binding to the Notch1 receptor, further releasing the Notch intracellular domain (NICD) to translocate into the nucleus, modulating the profibrotic genes expression and accelerating the lung fibrosis

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal fibrotic disease of the lung, characterized by extreme deposition of extracellular matrix (ECM) and destruction of the normal lung architecture [1]. Despite extensive research over the past 25 years, treatment options for IPF are limited to two recently approved drugs that slow down disease progression [5, 6]. We are in need of prevention and additional treatment strategies for this fatal lung disease. Pulmonary fibrosis is derived by initially repeated epithelial cell damage and subsequently progressive lung scarring that results in the formation of fibroblast and myofibroblast foci [7]. These foci secrete excessive ECM that is mainly composed of collagens, depositing in the lung interstitium and destructing the lung structure, which leads to respiratory failure and death [8]. Due to the complicated pathogenesis of pulmonary fibrosis, better identification of reliable biomarkers in the pulmonary fibrosis is needed to recognize new therapeutic targets for IPF diseases

Methods

Findings

Discussion

Conclusion