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Methylomic correlates of autophagy activity in cystic fibrosis.
Caution, Kyle; Pan, Alexander; Krause, Kathrin; Badr, Asmaa; Hamilton, Kaitlin; Vaidya, Anup; Gosu, Hawin; Daily, Kylene; Estfanous, Shady; Gavrilin, Mikhail A; Drew, Mark E; Cormet-Boyaka, Estelle; Chen, Xi; Frankhouser, David E; Bundschuh, Ralf; Yan, Pearlly; Dakhlallah, Duaa; Amer, Amal O.
Afiliação
  • Caution K; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Pan A; Genomics Shared Resource, Comprehensive Cancer Center, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Krause K; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Badr A; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Hamilton K; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Vaidya A; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Gosu H; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Daily K; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Estfanous S; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Gavrilin MA; Department of Internal Medicine, The Ohio State University, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Drew ME; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Cormet-Boyaka E; Department of Veterinary Biosciences, The Ohio State University, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Chen X; Department of Veterinary Biosciences, The Ohio State University, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Frankhouser DE; Genomics Shared Resource, Comprehensive Cancer Center, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Bundschuh R; Genomics Shared Resource, Comprehensive Cancer Center, USA; Department of Internal Medicine, The Ohio State University, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Yan P; Genomics Shared Resource, Comprehensive Cancer Center, USA; Department of Internal Medicine, The Ohio State University, USA; The Ohio State University, Columbus, OH 43210, USA.
  • Dakhlallah D; West Virginia University, Department of Microbiology, Immunology and Cell Biology, The Ohio State University, USA.
  • Amer AO; Department of Microbial Infection and Immunity, Infectious Diseases Institute, USA; The Ohio State University, Columbus, OH 43210, USA. Electronic address: amal.amer@osumc.edu.
J Cyst Fibros ; 18(4): 491-500, 2019 07.
Article em En | MEDLINE | ID: mdl-30737168
ABSTRACT
Autophagy is a highly regulated, biological process that provides energy during periods of stress and starvation. This conserved process also acts as a defense mechanism and clears microbes from the host cell. Autophagy is impaired in Cystic Fibrosis (CF) patients and CF mice, as their cells exhibit low expression levels of essential autophagy molecules. The genetic disorder in CF is due to mutations in the cystic fibrosis transmembrane conductance regulator (cftr) gene that encodes for a chloride channel. CF patients are particularly prone to infection by pathogens that are otherwise cleared by autophagy in healthy immune cells including Burkholderia cenocepacia (B. cenocepacia). The objective of this study is to determine the mechanism underlying weak autophagic activity in CF macrophages and find therapeutic targets to correct it. Using reduced representation bisulfite sequencing (RRBS) to determine DNA methylation profile, we found that the promoter regions of Atg12 in CF macrophages are significantly more methylated than in the wild-type (WT) immune cells, accompanied by low protein expression. The natural product epigallocatechin-3-gallate (EGCG) significantly reduced the methylation of Atg12 promoter improving its expression. Accordingly, EGCG restricted B. cenocepacia replication within CF mice and their derived macrophages by improving autophagy and preventing dissemination. In addition, EGCG improved the function of CFTR protein. Altogether, utilizing RRBS for the first time in the CF field revealed a previously unrecognized mechanism for reduced autophagic activity in CF. Our data also offers a mechanism by which EGCG exerts its positive effects in CF.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Fibrose Cística / Macrófagos Limite: Animals Idioma: En Revista: J Cyst Fibros Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Fibrose Cística / Macrófagos Limite: Animals Idioma: En Revista: J Cyst Fibros Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos