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

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.

Inhaled Lipid Nanoparticles Alleviate Established Pulmonary Fibrosis

“…We next performed immunofluorescence staining analysis of alpha‐smooth muscle actin (α‐SMA) and collagen I, which are important biomarkers of fibroblasts, in MLE‐12 cells after different treatments. [ 41 ] As shown in Figure 2d–f, compared to the TGF‐β1‐treated group, the Met‐liposome and Nint‐liposome groups exhibited slightly downregulated expression of α‐SMA and collagen I. Interestingly, both free drugs and Met/Nint‐liposome treatment exhibited markedly reduced fluorescence signals from α‐SMA and collagen I reduction in the fluorescence intensity, suggesting the synergistic therapeutic effect induced by metformin and nintedanib. To determine whether Met/Nint‐liposome could inhibit the secretion of pro‐inflammatory factors, enzyme‐linked immunosorbent assay (ELISA) was used to detect the levels of different inflammatory cytokines, including interleukin‐1β (IL‐1β) and interleukin‐6 (IL‐6), in MLE‐12 cells treated with PBS, TGF‐β1, TGF‐β1+ Free drugs, TGF‐β1+ Met‐liposome, TGF‐β1+ Nint‐liposome, and TGF‐β1+ Met/Nint‐liposome.…”

Identification of immune biomarkers associated with basement membranes in idiopathic pulmonary fibrosis and their pan-cancer analysis

“…It is reported that Notch signaling pathway plays a key role in the development, balance and regeneration of the respiratory system (Kiyokawa and Morimoto, 2020). The disorder of Notch signaling pathway is related to the occurrence of IPF, and the activation of Notch signaling can accelerate pulmonary fibrosis (Yang et al, 2022). Therefore, regulating the activation of Notch signaling pathway may be a new anti-fibrosis treatment strategy.…”

Induction of apoptosis and autophagy by dichloromethane extract from Patrinia scabiosaefolia Fisch on acute myeloid leukemia cells

“…The procedures for RNA extraction, cDNA synthesis, and quantitative real-time polymerase chain reaction (RT-PCR) followed the protocols delineated earlier. 18,19 GAPDH served as a normalizer. The relative mRNA expression of the target genes was determined utilizing the 2 ÀΔΔCt method.…”