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A Method for Measuring RNA N6-methyladenosine Modifications in Cells and Tissues
Published on: December 5, 2016
m6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity
Yanqin Qin1, Binghua Li2, Suyavaran Arumugam3
1Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
Abstract:
N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism, but its role in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity is not known. Here, we show that myeloid lineage-restricted deletion of the m6A "writer" protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Mechanistically, loss of METTL3 results in the differential expression of multiple mRNA transcripts marked with m6A, with a notable increase of DNA Damage Inducible Transcript 4 (DDIT4) mRNA level. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4. Taken together, our findings identify the contribution of METTL3-mediated m6A modification of Ddit4 mRNA to macrophage metabolic reprogramming in NAFLD and obesity.
Insights
Methyltransferase Like 3 (METTL3) protein regulates N6-methyladenosine (m6A) RNA modifications. Deleting METTL3 in myeloid cells prevents obesity and non-alcoholic fatty liver disease (NAFLD) by reprogramming macrophage metabolism.
Area of Science:
- Immunology
- Metabolism
- Epigenetics
Background:
- N6-methyladenosine (m6A) RNA modification impacts mRNA metabolism.
- The role of m6A in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity remains unclear.
Purpose of the Study:
- To investigate the role of the m6A writer protein METTL3 in NAFLD and obesity.
- To elucidate the underlying mechanisms of METTL3-mediated metabolic reprogramming in macrophages.
Main Methods:
- Myeloid lineage-restricted deletion of Methyltransferase Like 3 (METTL3) in mice.
- Analysis of age-related and diet-induced NAFLD and obesity development.
- Assessment of inflammatory and metabolic phenotypes.
- mRNA sequencing and analysis of m6A-modified transcripts, including DDIT4.
- Investigation of mTOR and NF-κB pathway activity in METTL3-deficient macrophages.
Main Results:
- Loss of METTL3 prevented NAFLD and obesity development in mice.
- METTL3 deficiency led to differential expression of m6A-marked mRNA transcripts, notably increasing DDIT4 mRNA.
- METTL3-deficient macrophages exhibited downregulated mTOR and NF-κB pathway activity.
- DDIT4 knockdown restored pathway activity in METTL3-deficient macrophages.
Conclusions:
- METTL3-mediated m6A modification of DDIT4 mRNA contributes to macrophage metabolic reprogramming.
- Targeting METTL3 may offer a therapeutic strategy for NAFLD and obesity.
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