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METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication
Rationale: Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. N(6)-methyladenosine (m(6)A) serves as the most prevalent modification in eukaryotic m...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8690932/ https://www.ncbi.nlm.nih.gov/pubmed/34987645 http://dx.doi.org/10.7150/thno.63441 |
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author | Suo, Long Liu, Chang Zhang, Qiu-Yang Yao, Mu-Di Ma, Yan Yao, Jin Jiang, Qin Yan, Biao |
author_facet | Suo, Long Liu, Chang Zhang, Qiu-Yang Yao, Mu-Di Ma, Yan Yao, Jin Jiang, Qin Yan, Biao |
author_sort | Suo, Long |
collection | PubMed |
description | Rationale: Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. N(6)-methyladenosine (m(6)A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m(6)A RNA modification in pericyte dysfunction is still unclear. Methods: Quantitative polymerase chain reactions and western blots were conducted to detect the change of m(6)A RNA modification in pericytes and mouse retinas following diabetic stress. MTT assay, transwell migration assay, caspase 3/7 activity assay, calcein-AM/propidium iodide (PI) staining, and TUNEL staining were conducted to determine the role of METTL3 in pericyte biology in vitro. Retinal trypsin digestion, vascular permeability assay, and IB4-NG2 double immunofluorescent staining were conducted to determine the role of METTL3 in retinal pericyte dysfunction and vascular complication. RNA sequencing, RNA pull-down assays and immunoblots were conducted to clarify the mechanism of METTL3-mediated pericyte dysfunction and vascular complication. Results: The levels of m(6)A RNA methylation were significantly up-regulated in pericytes and mouse retinas following diabetic stress, which were caused by increased expression of METTL3. METTL3 regulated the viability, proliferation, and differentiation of pericytes in vitro. Specific depletion of METTL3 in pericytes suppressed diabetes-induced pericyte dysfunction and vascular complication in vivo. METTL3 overexpression impaired pericyte function by repressing PKC-η, FAT4, and PDGFRA expression, which was mediated by YTHDF2-dependent mRNA decay. Conclusion: METTL3-mediated m(6)A methylation epigenetically regulates diabetes-induced pericyte dysfunction. METTL3-YTHDF2-PKC-η/FAT4/PDGFRA signaling axis could be therapeutically targeted for treating microvascular complications. |
format | Online Article Text |
id | pubmed-8690932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-86909322022-01-04 METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication Suo, Long Liu, Chang Zhang, Qiu-Yang Yao, Mu-Di Ma, Yan Yao, Jin Jiang, Qin Yan, Biao Theranostics Research Paper Rationale: Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. N(6)-methyladenosine (m(6)A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m(6)A RNA modification in pericyte dysfunction is still unclear. Methods: Quantitative polymerase chain reactions and western blots were conducted to detect the change of m(6)A RNA modification in pericytes and mouse retinas following diabetic stress. MTT assay, transwell migration assay, caspase 3/7 activity assay, calcein-AM/propidium iodide (PI) staining, and TUNEL staining were conducted to determine the role of METTL3 in pericyte biology in vitro. Retinal trypsin digestion, vascular permeability assay, and IB4-NG2 double immunofluorescent staining were conducted to determine the role of METTL3 in retinal pericyte dysfunction and vascular complication. RNA sequencing, RNA pull-down assays and immunoblots were conducted to clarify the mechanism of METTL3-mediated pericyte dysfunction and vascular complication. Results: The levels of m(6)A RNA methylation were significantly up-regulated in pericytes and mouse retinas following diabetic stress, which were caused by increased expression of METTL3. METTL3 regulated the viability, proliferation, and differentiation of pericytes in vitro. Specific depletion of METTL3 in pericytes suppressed diabetes-induced pericyte dysfunction and vascular complication in vivo. METTL3 overexpression impaired pericyte function by repressing PKC-η, FAT4, and PDGFRA expression, which was mediated by YTHDF2-dependent mRNA decay. Conclusion: METTL3-mediated m(6)A methylation epigenetically regulates diabetes-induced pericyte dysfunction. METTL3-YTHDF2-PKC-η/FAT4/PDGFRA signaling axis could be therapeutically targeted for treating microvascular complications. Ivyspring International Publisher 2022-01-01 /pmc/articles/PMC8690932/ /pubmed/34987645 http://dx.doi.org/10.7150/thno.63441 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Suo, Long Liu, Chang Zhang, Qiu-Yang Yao, Mu-Di Ma, Yan Yao, Jin Jiang, Qin Yan, Biao METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication |
title | METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication |
title_full | METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication |
title_fullStr | METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication |
title_full_unstemmed | METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication |
title_short | METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication |
title_sort | mettl3-mediated n(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8690932/ https://www.ncbi.nlm.nih.gov/pubmed/34987645 http://dx.doi.org/10.7150/thno.63441 |
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