A methionine-Mettl3-N-methyladenosine axis promotes polycystic kidney disease

Yin

et al. 2021

Preprint

Hepatic glycogen is the main source of blood glucose and controls the intervals between meals in mammals. Hepatic glycogen storage in mammalian pups is insufficient compared to their adult counterparts; however, the detailed molecular mechanism is poorly understood. Here, we showed that, similar to glycogen storage pattern, N6-methyladenosine (m6A) modification in mRNAs gradually increases during the growth of mice in liver. Strikingly, in the liver-specific Mettl3 knockout mice, loss of m6A modification disrupts liver glycogen storage. On the mechanism, we screened and identified that glycogen synthase 2 (Gys2) plays a critical role in m6A-mediated regulation of liver glycogen storage. Furthermore, IGF2BP2, as a “reader” of m6A, stabilizes the mRNA of Gys2. More importantly, reconstitution of GYS2 rescues liver glycogenesis in Mettl3-cKO mice. Collectively, a METTL3-IGF2BP2-GYS2 axis, in which METTL3 and IGF2BP2 regulate glycogenesis as “writer” and “reader” respectively, plays a critical role on maintenance of liver glycogenesis in mammals.

Section: Introductionmentioning

confidence: 84%

N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA

Yin

et al. 2021

Preprint

“…In an ADPKD mouse model, SAM supplementation aggravated cyst growth by upregulating Mettl3 expression. In contrast, a methionine-restricted diet reduced kidney size and cysts compared with a standard diet by inducing the expression of Mettl3 [ 132 ]. Although the underlying mechanism by which SAM and methionine regulate Mettl3 expression is unclear, this study links methionine utilization to epitranscriptome activation of disease progression.…”

Section: Modulation Of Sam/sah Levels To Influence the Function Of M6a Methyltransferasesmentioning

confidence: 99%

N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

et al. 2021

N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.

“…One possible mechanism is through the impact of one-carbon and methionine metabolism which generate the essential methyl groups for which altered nutrient utilization is facilitated. Ramalingam et al found a higher methionine-S-adenosyl methionine (SAM) levels and methyltransferase-like 3 (Mettl3) upregulation in multiple ADPKD mouse models and that methionine-SAM supplementation or Mettl3 overexpression induced cyst growth ( 133 ). Dietary methionine restriction or Mettl3 ablation attenuated PKD, which may be regulated through epitranscriptomic mechanism through c-Myc and cAMP signaling activation ( 133 ).…”

Section: Systems Biology Of Adpkdmentioning

confidence: 99%

“…Ramalingam et al found a higher methionine-S-adenosyl methionine (SAM) levels and methyltransferase-like 3 (Mettl3) upregulation in multiple ADPKD mouse models and that methionine-SAM supplementation or Mettl3 overexpression induced cyst growth ( 133 ). Dietary methionine restriction or Mettl3 ablation attenuated PKD, which may be regulated through epitranscriptomic mechanism through c-Myc and cAMP signaling activation ( 133 ). As for therapy, a vegan-based diet could also be used to ameliorate cyst formation, as methionine is found in meat and fish; alternatively, METTL3 inhibitors may also be targetable for ADPKD but warrants further investigation.…”

Section: Systems Biology Of Adpkdmentioning

confidence: 99%

Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD

Pagliarini

Podrini

2021

Front. Med.

Metabolic reprogramming is a key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD) characterized by changes in cellular pathways occurring in response to the pathological cell conditions. In ADPKD, a broad range of dysregulated pathways have been found. The studies supporting alterations in cell metabolism have shown that the metabolic preference for abnormal cystic growth is to utilize aerobic glycolysis, increasing glutamine uptake and reducing oxidative phosphorylation, consequently resulting in ADPKD cells shifting their energy to alternative energetic pathways. The mechanism behind the role of the polycystin proteins and how it leads to disease remains unclear, despite the identification of numerous signaling pathways. The integration of computational data analysis that accompanies experimental findings was pivotal in the identification of metabolic reprogramming in ADPKD. Here, we summarize the important results and argue that their exploitation may give further insights into the regulative mechanisms driving metabolic reprogramming in ADPKD. The aim of this review is to provide a comprehensive overview on metabolic focused studies and potential targets for treatment, and to propose that computational approaches could be instrumental in advancing this field of research.