Pancreatic agenesis and altered m6A methylation in the pancreas of PDX1-mutant cynomolgus macaquesOACSTPCD
As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell function.Mutations in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal diabetes mellitus.However,the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models.In this study,three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology,all of which succumbed shortly postpartum,exhibiting pancreatic agenesis.Notably,one tri-allelic PDX1-mutant cynomolgus macaque(designated as M4)developed a pancreas,whereas the two monoallelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation.RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions,indicating developmental delay and PDX1haploinsufficiency.A marked change in m6A methylation was identified in the M4 pancreas,confirmed through cultured PDX1-mutantisletorganoids.Notably,overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids.This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.
Wen-Hui Zhang;Jiong-Han Zhuang;Yun-Yi Guo;Xue-Ying Chen;Ya-Qing Li;Jie-Qiu Xu;An-Ran Zhang;Bao-Yi Chen;Wei Meng;Yan-Hua Zhu;Jun-Jiu Huang;Yong-Long Guo;Shi-Hua Yang
College of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,China College of Coastal Agricultural Sciences,Guangdong Ocean University,Zhanjiang,Guangdong 524088,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaDepartment of Endocrinology and Metabolism,Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,510630,China Guangdong Provincial Key Laboratory of Diabetology,Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 510630,China Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research,Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 510630,ChinaKey Laboratory of Reproductive Medicine of Guangdong Province,School of Life Sciences and First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510275,China MOE Key Laboratory of Gene Function and Regulation,State Key Laboratory of Biocontrol,School of Life Sciences,Sun Yat-sen University,Guangzhou,Guangdong 510275,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,ChinaCollege of Veterinary Medicine,South China Agricultural University,Guangzhou,Guangdong 510642,China
生物学
PDX1MODY4Cynomolgus macaquesM6A methylation modification
《Zoological Research》 2024 (6)
P.1188-1200,13
supported by the National Key R&D Program of China(2018YFA0801404,2023YFC3403400)National Natural Science Foundation of China(81941006,32371190,32370878)Guangdong Special Support Program(2019BT02Y276,2024A1515012868)Double First-Class Discipline Promotion Project(2023B10564003)Program for Scientific Research Start-up Funds of Guangdong Ocean University(060302052408)。
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