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Review
. 2022 Dec 16;13(12):2381.
doi: 10.3390/genes13122381.

RNA Epigenetics in Chronic Lung Diseases

Xiaorui Wang  1 , Zhihou Guo  2 , Furong Yan  2
Affiliations
Review

RNA Epigenetics in Chronic Lung Diseases

Xiaorui Wang et al. Genes (Basel). .

Abstract

Chronic lung diseases are highly prevalent worldwide and cause significant mortality. Lung cancer is the end stage of many chronic lung diseases. RNA epigenetics can dynamically modulate gene expression and decide cell fate. Recently, studies have confirmed that RNA epigenetics plays a crucial role in the developing of chronic lung diseases. Further exploration of the underlying mechanisms of RNA epigenetics in chronic lung diseases, including lung cancer, may lead to a better understanding of the diseases and promote the development of new biomarkers and therapeutic strategies. This article reviews basic information on RNA modifications, including N6 methylation of adenosine (m6A), N1 methylation of adenosine (m1A), N7-methylguanosine (m7G), 5-methylcytosine (m5C), 2'O-methylation (2'-O-Me or Nm), pseudouridine (5-ribosyl uracil or Ψ), and adenosine to inosine RNA editing (A-to-I editing). We then show how they relate to different types of lung disease. This paper hopes to summarize the mechanisms of RNA modification in chronic lung disease and finds a new way to develop early diagnosis and treatment of chronic lung disease.

Keywords: RNA epigenetics; RNA methylation; chronic lung disease; lung cancer; treatment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
The mechanisms and pathways of RNA modifications in lung cancer. The RNA modifications that have been confirmed to be involved in the development and progression of lung cancer include m6A, m7G, m5C, Ψ, and A to I editing. The most studied modification in lung cancer is m6A. METTL3 increases the expression of YAP mRNA by combining YTHDF1/3-eIF3b axis and MALAT1-miR-1914 axis, causing drug resistance and metastasis of lung cancer. The m6A-modified PDK4 mRNA enhances cellular glycolysis through IGF2BP3, thereby promoting tumor growth. The knockdown of METTL14 reversed this process. USP7 mRNA or MZF1 mRNA demethylated by FTO can promote the tumor growth. IGF2BP1 can promote drug resistance and tumor growth by stabilizing oncogenic mRNAs. METTL3 induces the maturation of miR-143 and inhibits the expression of Vasohibin-1, thereby inducing lung cancer brain metastasis. METTL14 regulates the expression of lncRNA HCG11 and then inhibits tumor growth by targeting LATS1 mRNA via IGF2BP2. The m7G methyltransferase METTL1 and WDR4 complex promotes the tumor growth and invasion. In addition, METTTL1 promotes the methylation of Let-7 miRNA, increases the expression of HMGA2, RAS and MYC, and induces the tumor metastasis. The m5C-associated upregulations of NSUN3 and NSUN4 are associated with poor prognosis. Cancer cells with high NSUN1 expression are related with poor differentiated. LncRNA PCAT1 and Ψ methyltransferase DKC1 cooperate to promote the proliferation, invasion and apoptosis of lung cancer cells. ADAR promotes tumor progression by stabilizing FAK transcripts. The expression of Ψ methyltransferase PUS10 is associated with the tumor growth. A-to-I miRNA editing correlates with tumor phenotype.
Figure 1
Figure 1
The most common types of RNA modifications. Common RNA modifications include N6 methylation of adenosine (m6A), N1 methylation of adenosine (m1A), N7-methylguanosine (m7G), 5-methylcytosine (m5C), 2′O-methylation (2′-O-Me), pseudouridine (Ψ), and adenosine to inosine RNA editing (A-to-I editing), and regulated by methyltransferase (writers), demethylases (erasers), and some specific proteins (readers).
Figure 3
Figure 3
The mechanisms and pathways of RNA modifications in chronic lung diseases. RNA modifications promote the occurrence and development of chronic lung diseases such as COPD, pneumonia, asthma, and pulmonary fibrosis. Among these modifications, m6A have been the most studied in chronic lung diseases. The mRNA expressions of m6A related IGF2BP3, FTO, METTL3 and YTHDC2 promote the progression of COPD. The m6A methyltransferase METTL16 regulates the level of sulfate and participates in microvascular injury induced by PM2.5. In addition, increased m5C modification is also involved in the process of PM2.5 induced COPD by inhibiting lung metabolic activity. LncRNA SNHG4 promotes LPS-induced pneumonia by inhibiting METTL3-mediated STAT2 mRNA expression. The enhancement of FMT promotes pulmonary fibrosis. METTL3 increases the FMT process. The m6A modification also is involved in FMT process by regulating KCNH6 expression through YTHDF1. METTL1 level in IPF patients is positive associated with poor prognosis. ALKBH5 promotes silicon-induced pulmonary fibrosis through FOXM1. The m6A-related YTHDF3 causes severe asthma by affecting eosinophils.
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Grants and funding

This work was funded by The National Natural Science Foundation of China (Grant number: 82200043); Quanzhou City Science & Technology Program of China (Grant number: 2018N008S); Natural Science Foundation of Fujian Province (Grant number: 2020J05052); Startup Fund for Scientific Research, Fujian Medical University (Grant No. 2019QH1121).