METTL3-m6A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease

Peng, Zishan; Gong, Yingying; Wang, Xuejie; He, Weiman; Wu, Li; Zhang, Luyao; Xiong, Li; Huang, Yanrui; Su, Lei; Shi, Peijie; Cao, Xiaopei; Liu, Rengyun; Li, Yanbing; Xiao, Hang

doi:10.1016/j.ymthe.2021.09.016

Cited by 56 publications

(37 citation statements)

References 56 publications

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“…Altered autophagy or autophagic protein function results in maladaptive inflammatory and metabolic responses, therefore causing the development of more severe diseases ( 36 ). Various pathophysiological conditions have identified different m6A modifications regulating aberrant autophagy ( 34 , 37 – 39 ).…”

Section: Discussionmentioning

confidence: 99%

Alterations of m6A RNA methylation regulators contribute to autophagy and immune infiltration in primary Sjögren’s syndrome

Cheng

Li²,

Zhan³

et al. 2022

Front. Immunol.

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N6-methyladenosine (m6A) RNA modification is a new epigenetic regulation mechanism on eukaryotic mRNA. Few autoimmune diseases focused on the role of m6A in their pathogenies, and m6A modulation in the pathological process of primary Sjögren’s syndrome (pSS) is still unknown. In this work, three microarray datasets of pSS patients were downloaded from the GEO database: datasets #1 and #2 from the whole peripheral blood (PB) samples, dataset #3 from the labial salivary gland tissue samples, as well as a PB cohort collected from our hospital. Six differentially expressed m6A regulators were identified by comparing the PB dataset #1 of pSS and healthy controls using the Wilcox test and logistic regression analysis. Among them, four (ALKBH5, RBMX, RBM15B, and YTHDF1) were confirmed as down-regulated in PB dataset #2 and in our PB cohort by RT-PCR, and four (ALKBH5, METTL3, RBM15B, and YTHDF1) were confirmed as down-regulated in the dataset #3 of the labial gland tissue. In addition, discrepantly expressed m6A regulators accompanied by diverse immunocytes, including dendritic cells (DCs), T cells, and CD56dim natural killer cells, and among the regulators, ALKBH5 and METTL3 were comprehensively linked with the infiltrated immune cells. Notably, the most enriched autophagy mechanism mediated by m6A was observed in pSS using functional annotation analysis. Ten hub genes were identified using a protein-protein interaction network, and their expression in PB dataset #2 and the expression of three genes (PIK3CA, STAT1, and MAPK3) in the labial gland tissue dataset #3 were confirmed. Our study provides evidence that m6A methylation is widely involved in the immune infiltration and autophagy of pSS, thus contributing to the pathogenesis of this disease and potentially representing a novel therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Alterations of m6A RNA methylation regulators contribute to autophagy and immune infiltration in primary Sjögren’s syndrome

Cheng

Li²,

Zhan³

et al. 2022

Front. Immunol.

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“…Autophagy also plays a role in RNA m6A methylation of the NAFLD progression. METTL3 and its partner YTHDF1 inhibit the autophagic flux in hepatocytes and block the clearance of lipid droplets by the means of promoting the stability of Rubicon mRNA, which inhibited the autophagy process of autophagosome-lysosome fusion ( 80 ).…”

Section: M6a Methylation and Lipid-related Metabolic Diseasesmentioning

confidence: 99%

“…NAFLD is a complex metabolic disease and many pathological changes happened in liver tissue ( 94 ).The RNA m6A methylation regulator FTO, METTL3, and the recognition protein family YTHDF affect the progression of NAFLD to hepatocellular carcinoma (HCC) by the means of disorder lipid metabolism, oxidative stress ( 87 ), and autophagy ( 80 ), making it an important potential treatment target. Altering the RNA m6A methylation level of various proteins reduces the hepatic abnormal lipid accumulation, thereby further relieving the abnormal state of cells.…”

Section: M6a Methylation and Lipid-related Metabolic Diseasesmentioning

confidence: 99%

The role of RNA m6A methylation in lipid metabolism

Wang

et al. 2022

Front. Endocrinol.

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The m6A methylation is the most numerous modification of mRNA in mammals, coordinated by RNA m6A methyltransferases, RNA m6A demethylases, and RNA m6A binding proteins. They change the RNA m6A methylation level in their specific manner. RNA m6A modification has a significant impact on lipid metabolic regulation. The “writer” METTL3/METTL14 and the “eraser” FTO can promote the accumulation of lipids in various cells by affecting the decomposition and synthesis of lipids. The “reader” YTHDF recognizes m6A methylation sites of RNA and regulates the target genes’ translation. Due to this function that regulates lipid metabolism, RNA m6A methylation plays a pivotal role in metabolic diseases and makes it a great potential target for therapy.

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“…To date, further studies on the function of m 6 A-related enzymes confirmed that abnormal activity of these genes led to abnormal expression of thousands of genes, firmly suggesting an important role of m 6 A in RNA metabolism. Specifically, m 6 A may affect lipid metabolism [ 90 ], sperm development [ 91 ], tumorigenesis, stem cell-directed differentiation [ 92 ], cellular reprogramming [ 93 ], biological clock rhythms, cell division, memory, and neurodevelopment [ 94 ], as well as several other life processes. Therefore, given the critical role of m 6 A in the regulation of epigenetic events, these classes of enzymes have been identified to be involved in a variety of cellular life activities, particularly in the normal regulation of hematopoiesis in the hematological system ( Figure 3 ).…”

Section: M 6 a Methylation Modification And Normal Hematopoietic Regulationmentioning

confidence: 99%

The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

Zhao

Peng

2022

Cancers

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Epigenetics is identified as the study of heritable modifications in gene expression and regulation that do not involve DNA sequence alterations, such as DNA methylation, histone modifications, etc. Importantly, N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications of eukaryotic messenger RNA (mRNA), which plays a key role in various cellular processes. It can not only mediate various RNA metabolic processes such as RNA splicing, translation, and decay under the catalytic regulation of related enzymes but can also affect the normal development of bone marrow hematopoiesis by regulating the self-renewal, proliferation, and differentiation of pluripotent stem cells in the hematopoietic microenvironment of bone marrow. In recent years, numerous studies have demonstrated that m6A methylation modifications play an important role in the development and progression of hematologic malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes [MDS], multiple myeloma [MM], etc.). Targeting the inhibition of m6A-associated factors can contribute to increased susceptibility of patients with hematologic malignancies to therapeutic agents. Therefore, this review elaborates on the biological characteristics and normal hematopoietic regulatory functions of m6A methylation modifications and their role in the pathogenesis of hematologic malignancies.

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METTL3-m6A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease

Cited by 56 publications

References 56 publications

Alterations of m6A RNA methylation regulators contribute to autophagy and immune infiltration in primary Sjögren’s syndrome

Alterations of m6A RNA methylation regulators contribute to autophagy and immune infiltration in primary Sjögren’s syndrome

The role of RNA m6A methylation in lipid metabolism

The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

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