Methylation Microarray Studies Highlight PDGFA Expression as a Factor in Biliary Atresia
| Autor: | Randolph P. Matthews, John W. Tobias, Shuang Cui, Hakon Hakonarson, Zenobia C. Cofer, Steven F. EauClaire, Cecilia Kim, Kathleen M. Loomes |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Microarray Microarrays lcsh:Medicine Pathogenesis Pathology and Laboratory Medicine Biochemistry Larvae Cell Signaling Medicine and Health Sciences lcsh:Science Zebrafish Regulation of gene expression Platelet-Derived Growth Factor Multidisciplinary DNA methylation biology Fishes Nuclear Proteins Methylation Animal Models Hedgehog signaling pathway Chromatin 3. Good health Up-Regulation Nucleic acids Bioassays and Physiological Analysis Liver Osteichthyes Vertebrates Epigenetics DNA modification Chromatin modification Research Article Chromosome biology Signal Transduction Cell biology animal structures Kruppel-Like Transcription Factors Surgical and Invasive Medical Procedures Zinc Finger Protein Gli2 Research and Analysis Methods 03 medical and health sciences Digestive System Procedures Model Organisms Biliary Atresia GLI2 Genetics Animals Humans Hedgehog Proteins Transplantation Biology and life sciences Metamorphosis lcsh:R Organisms DNA Organ Transplantation biology.organism_classification Molecular biology Liver Transplantation 030104 developmental biology Gene Expression Regulation Genetic Loci Cancer research Hedgehog Signaling lcsh:Q Bile Ducts Gene expression DNA hypomethylation Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 3, p e0151521 (2016) |
| ISSN: | 1932-6203 |
| Popis: | Biliary atresia (BA) is a progressive fibro-inflammatory disorder that is the leading indication for liver transplantation in children. Although there is evidence implicating genetic, infectious, environmental, and inflammatory causes, the etiology of BA remains unknown. We have recently reported that cholangiocytes from BA patients showed decreased DNA methylation relative to disease- and non-disease controls, supporting a potential role for DNA hypomethylation in BA etiopathogenesis. In the current study, we examined the methylation status of specific genes in human BA livers using methylation microarray technology. We found global DNA hypomethylation in BA samples as compared to disease- and non-disease controls at specific genetic loci. Hedgehog pathway members, SHH and GLI2, known to be upregulated in BA, were both hypomethylated, validating this approach as an investigative tool. Another region near the PDGFA locus was the most significantly hypomethylated in BA, suggesting potential aberrant expression. Validation assays confirmed increased transcriptional and protein expression of PDGFA in BA livers. We also show that PDGF-A protein is specifically localized to cholangiocytes in human liver samples. Injection of PDGF-AA protein dimer into zebrafish larvae caused biliary developmental and functional defects. In addition, activation of the Hedgehog pathway caused increased expression of PDGF-A in zebrafish larvae, providing a previously unrecognized link between PDGF and the Hedgehog pathway. Our findings implicate DNA hypomethylation as a specific factor in mediating overexpression of genes associated with BA and identify PDGF as a new candidate in BA pathogenesis. |
| Databáze: | OpenAIRE |
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