@article{3794e6da9d4843e7953ecf81c3b74932,
title = "A methionine-Mettl3-N6-methyladenosine axis promotes polycystic kidney disease",
abstract = "Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder marked by numerous progressively enlarging kidney cysts. Mettl3, a methyltransferase that catalyzes the abundant N6-methyladenosine (m6A) RNA modification, is implicated in development, but its role in most diseases is unknown. Here, we show that Mettl3 and m6A levels are increased in mouse and human ADPKD samples and that kidney-specific transgenic Mettl3 expression produces tubular cysts. Conversely, Mettl3 deletion in three orthologous ADPKD mouse models slows cyst growth. Interestingly, methionine and S-adenosylmethionine (SAM) levels are also elevated in ADPKD models. Moreover, methionine and SAM induce Mettl3 expression and aggravate ex vivo cyst growth, whereas dietary methionine restriction attenuates mouse ADPKD. Finally, Mettl3 activates the cyst-promoting c-Myc and cAMP pathways through enhanced c-Myc and Avpr2 mRNA m6A modification and translation. Thus, Mettl3 promotes ADPKD and links methionine utilization to epitranscriptomic activation of proliferation and cyst growth.",
keywords = "AVPR2, METTL3, N-methyladenosine, S-adenosylmethionine, c-Myc, m6A mRNA methylation, mRNA translation, methionine, polycystic kidney disease",
author = "Harini Ramalingam and Sonu Kashyap and Patricia Cobo-Stark and Andrea Flaten and Chang, {Chun Mien} and Sachin Hajarnis and Hein, {Kyaw Zaw} and Jorgo Lika and Warner, {Gina M.} and Espindola-Netto, {Jair M.} and Ashwani Kumar and Mohammed Kanchwala and Chao Xing and Chini, {Eduardo N.} and Vishal Patel",
note = "Funding Information: The work is supported by the National Institutes of Health ( R01DK102572 ) to V.P. and a PKD Foundation Research Grant Award to (E.N.C. and S.K.). H.R. is supported by the PKD Foundation Research Fellowship. We thank the O'Brien Kidney Research Core Center ( P30DK079328 ) at UT Southwestern Medical Center (UTSW), the Eugene McDermott Center for Human Growth and Development Sequencing Core and Bioinformatics Lab at UTSW, the UTSW Molecular Pathology Core, and the Whole Brain Microscopy Facility at UTSW for providing critical reagents and services. Human ADPKD and normal human kidney cells and tissues were provided by the PKD Biomarkers, Biomaterials and Cellular Models Core, located at the University of Kansas Medical Center. The Core is part of the PKD Research Resource Consortium, supported by the National Institutes of Health/ NIDDK ( U54 DK126126 ). We thank Dr. Ronak Lakhia and Dr. Abheepsa Mishra for their critical review and valuable inputs on the manuscript. Funding Information: The work is supported by the National Institutes of Health (R01DK102572) to V.P. and a PKD Foundation Research Grant Award to (E.N.C. and S.K.). H.R. is supported by the PKD Foundation Research Fellowship. We thank the O'Brien Kidney Research Core Center (P30DK079328) at UT Southwestern Medical Center (UTSW), the Eugene McDermott Center for Human Growth and Development Sequencing Core and Bioinformatics Lab at UTSW, the UTSW Molecular Pathology Core, and the Whole Brain Microscopy Facility at UTSW for providing critical reagents and services. Human ADPKD and normal human kidney cells and tissues were provided by the PKD Biomarkers, Biomaterials and Cellular Models Core, located at the University of Kansas Medical Center. The Core is part of the PKD Research Resource Consortium, supported by the National Institutes of Health/NIDDK (U54 DK126126). We thank Dr. Ronak Lakhia and Dr. Abheepsa Mishra for their critical review and valuable inputs on the manuscript. H.R. P.C.-S. S.H. S.K. G.M.W. E.N.C. and V.P. designed research. H.R. P.C.-S. A.F. S.K. S.H. C.H. K.Z.H. J.L. and J.M.E. performed experiments. H.R. P.C.-S. A.F. S.H. S.K. E.C. and V.P. interpreted the data. A.K. M.K. and C.X. performed the bioinformatics analysis. H.R. S.K. E.N.C. and V.P. prepared the figures. H.R. and V.P. wrote the manuscript. All the authors contributed critical edits to the paper. E.N.C has a patent on the use of PAPP-A inhibitors in ADPKD. E.N.C. is a consultant for TeneoBio, Calico, Mitobridge, and Cytokinetics. E.N.C. is on the advisory board of Eolo Pharma. E.N.C. owns stocks in Teneobio. Unrelated to this work, V.P. has patents involving the use of anti-miR-17 for the treatment of ADPKD (16/466,752 and 15/753,865). V.P. has previously held investment interests in Regulus Therapeutics and serves as a consultant for Otsuka Pharmaceuticals. V.P. lab has a sponsored research agreement with Regulus Therapeutics (unrelated to this work). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "1",
doi = "10.1016/j.cmet.2021.03.024",
language = "English (US)",
volume = "33",
pages = "1234--1247.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}