m6A RNA modification controls autophagy through upregulating ULK1 protein abundance

Jin, Shouheng; Zhang, Xiya; Miao, Yanyan; Liang, Puping; Zhu, Kaiyu; She, Yuanchu; Wu, Yiming; Liu, Di-Ao; Huang, Junjiu; Ren, Jian; Cui, Jun

doi:10.1038/s41422-018-0069-8

Cited by 100 publications

(95 citation statements)

References 10 publications

(27 reference statements)

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“…In addition, several groups have found that m6A regulates circRNA translation efficiency, 43 microRNA biogenesis 44 and autophagy. 45 F I G U R E 7 A model illustrating FTOmediated PGC-1α expression and mitochondrial activity in ccRCC cells. FTO mediates demethylation of adenosine residues in the 3′-UTR of PGC-1α mRNA, leading to increased PGC-1α mRNA stability and protein expression, and increased mitochondrial biogenesis, oxidative stress and tumour suppression…”

Section: Discussionmentioning

confidence: 99%

N6‐methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO‐PGC‐1α signalling axis

Zhuang

Luo

et al. 2019

J Cellular Molecular Medi

115

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The abundant and reversible N6‐methyladenosine (m6A) R NA modification and its modulators have important roles in regulating various gene expression and biological processes. Here, we demonstrate that fat mass and obesity associated ( FTO ), as an m6A demethylase, plays a critical anti‐tumorigenic role in clear cell renal cell carcinoma (cc RCC ). FTO is suppressed in cc RCC tissue. The low expression of FTO in human cc RCC correlates with increased tumour severity and poor patient survival. The Von Hippel‐Lindau‐deficient cells expressing FTO restores mitochondrial activity, induces oxidative stress and ROS production and shows impaired tumour growth, through increasing expression of PGC ‐1α by reducing m6A levels in its mRNA transcripts. Our work demonstrates the functional importance of the m6A methylation and its modulator, and uncovers a critical FTO ‐ PGC ‐1α axis for developing effective therapeutic strategies in the treatment of cc RCC .

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Section: Discussionmentioning

confidence: 99%

N6‐methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO‐PGC‐1α signalling axis

Zhuang

Luo

et al. 2019

J Cellular Molecular Medi

115

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“…In addition, recent studies described a new role for IMP proteins as "readers" of N 6methyladenosine (m 6 A) modified mRNAs [27]. This is intriguing, as emerging studies suggest that autophagy transcripts may be controlled by m 6 A modification [62]. It is therefore likely that IMP1 may modulate the autophagy pathway via multiple mechanisms, which provides one explanation as to why we observe direct binding of some, but not all autophagy transcripts in RIP assays for IMP1 in colon cancer cell lines.…”

Section: Transcriptmentioning

confidence: 99%

Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP 1/ IGF 2 BP 1

et al. 2019

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RNA binding proteins, including IMP1/IGF2BP1, are essential regulators of intestinal development and cancer. Imp1 hypomorphic mice exhibit gastrointestinal growth defects, yet the specific role for IMP1 in colon epithelial repair is unclear. Our prior work revealed that intestinal epithelial cell‐specific Imp1 deletion (Imp1ΔIEC) was associated with better regeneration in mice after irradiation. Here, we report increased IMP1 expression in patients with Crohn's disease and ulcerative colitis. We demonstrate that Imp1ΔIEC mice exhibit enhanced recovery following dextran sodium sulfate (DSS)‐mediated colonic injury. Imp1ΔIEC mice exhibit Paneth cell granule changes, increased autophagy flux, and upregulation of Atg5. In silico and biochemical analyses revealed direct binding of IMP1 to MAP1LC3B, ATG3, and ATG5 transcripts. Genetic deletion of essential autophagy gene Atg7 in Imp1ΔIEC mice revealed increased sensitivity of double‐mutant mice to colonic injury compared to control or Atg7 single mutant mice, suggesting a compensatory relationship between Imp1 and the autophagy pathway. The present study defines a novel interplay between IMP1 and autophagy, where IMP1 may be transiently induced during damage to modulate colonic epithelial cell responses to damage.

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“…Recently, m6A modi cation was reported to inhibit autophagy activity in several cellular contexts [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying mechanism on the role of m6A in blastocyst development remains unclear. Of note, the phenomena of m6A modi cation negatively correlating with autophagy activity have been clearly documented in several different cellular contexts [26][27][28]. We thus hypothesized that METTL3-mediated m6A methylation might regulate blastocyst development via repressing autophagy activity.…”

Section: Introductionmentioning

confidence: 90%

METTL3-mediated m6A methylation negatively modulates autophagy to support blastocyst development

Cao

Zhang

Hong

et al. 2020

Preprint

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Background: N6-methyladenosine (m6A) catalyzed by METTL3 regulates the maternal-to-zygotic transition in zebrafish and mice. However, the role and mechanism of METTL3-mediated m6A methylation in blastocyst development remains unclear. Results: We found that reduced m6A levels triggered by METTL3 knockdown caused embryonic arrest during morula-blastocyst transition and developmental defects in trophectoderm cells. Intriguingly, overexpression of METTL3 in early embryos resulted in increased m6A levels and these embryos phenocopied METTL3 knockdown embryos. Mechanistically, METTL3 knockdown or overexpression resulted in a significant increase or decrease in expression of ATG5 and LC3 (an autophagy marker) in blastocysts, respectively. m6A modification of ATG5 mRNA mainly occurs at 3’UTR, and METTL3 knockdown enhanced ATG5 mRNA stability, suggesting that METTL3 negatively regulated autophagy in an m6A dependent manner. Furthermore, single-cell analysis revealed that METTL3 knockdown only increased expression of LC3 and ATG5 in trophectoderm cells, indicating preferential inhibitory effects of METTL3 on autophagy activity in the trophectoderm lineage. Importantly, autophagy restoration by 3MA (an autophagy inhibitor) treatment partially rescued developmental defects of METTL3 knockdown blastocysts. Conclusions: Our results demonstrate that METTL3-mediated m6A methylation negatively modulates autophagy to support blastocyst development.

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m6A RNA modification controls autophagy through upregulating ULK1 protein abundance

Cited by 100 publications

References 10 publications

N6‐methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO‐PGC‐1α signalling axis

N6‐methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO‐PGC‐1α signalling axis

Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP 1/ IGF 2 BP 1

METTL3-mediated m6A methylation negatively modulates autophagy to support blastocyst development

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