Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins
The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing th...
Guardado en:
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2015
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257974_v94_n36_p_Pirola http://hdl.handle.net/20.500.12110/paper_00257974_v94_n36_p_Pirola |
| Aporte de: |
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paper:paper_00257974_v94_n36_p_Pirola |
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dspace |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
5 hydroxymethylcytosine cytokeratin 18 messenger RNA mitochondrial DNA peptides and proteins peroxisome proliferator activated receptor gamma coactivator 1alpha ten eleven translocation 1 protein ten eleven translocation 2 protein ten eleven translocation 3 protein unclassified drug 5-hydroxymethylcytosine cytosine DNA binding protein heat shock protein oncoprotein PPARGC1A protein, human TET1 protein, human transcription factor abdominal obesity adult apoptosis Article controlled study disease severity DNA methylation DNA modification epigenetics female gene dosage gene locus genetic susceptibility genetic variability histopathology human human tissue hypertension hypertriglyceridemia immunohistochemistry insulin resistance liver biopsy liver fibrosis liver histology liver mitochondrion major clinical study male middle aged mitochondrial genome next generation sequencing non insulin dependent diabetes mellitus nonalcoholic fatty liver observational study priority journal protein expression protein methylation single nucleotide polymorphism steatosis analogs and derivatives genetic epigenesis genetic predisposition genetics liver metabolism Non-alcoholic Fatty Liver Disease organelle biogenesis pathology Adult Cytosine DNA Methylation DNA-Binding Proteins Epigenesis, Genetic Female Genetic Predisposition to Disease Heat-Shock Proteins Humans Liver Male Middle Aged Mitochondria, Liver Non-alcoholic Fatty Liver Disease Organelle Biogenesis Proto-Oncogene Proteins Transcription Factors |
| spellingShingle |
5 hydroxymethylcytosine cytokeratin 18 messenger RNA mitochondrial DNA peptides and proteins peroxisome proliferator activated receptor gamma coactivator 1alpha ten eleven translocation 1 protein ten eleven translocation 2 protein ten eleven translocation 3 protein unclassified drug 5-hydroxymethylcytosine cytosine DNA binding protein heat shock protein oncoprotein PPARGC1A protein, human TET1 protein, human transcription factor abdominal obesity adult apoptosis Article controlled study disease severity DNA methylation DNA modification epigenetics female gene dosage gene locus genetic susceptibility genetic variability histopathology human human tissue hypertension hypertriglyceridemia immunohistochemistry insulin resistance liver biopsy liver fibrosis liver histology liver mitochondrion major clinical study male middle aged mitochondrial genome next generation sequencing non insulin dependent diabetes mellitus nonalcoholic fatty liver observational study priority journal protein expression protein methylation single nucleotide polymorphism steatosis analogs and derivatives genetic epigenesis genetic predisposition genetics liver metabolism Non-alcoholic Fatty Liver Disease organelle biogenesis pathology Adult Cytosine DNA Methylation DNA-Binding Proteins Epigenesis, Genetic Female Genetic Predisposition to Disease Heat-Shock Proteins Humans Liver Male Middle Aged Mitochondria, Liver Non-alcoholic Fatty Liver Disease Organelle Biogenesis Proto-Oncogene Proteins Transcription Factors Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins |
| topic_facet |
5 hydroxymethylcytosine cytokeratin 18 messenger RNA mitochondrial DNA peptides and proteins peroxisome proliferator activated receptor gamma coactivator 1alpha ten eleven translocation 1 protein ten eleven translocation 2 protein ten eleven translocation 3 protein unclassified drug 5-hydroxymethylcytosine cytosine DNA binding protein heat shock protein oncoprotein PPARGC1A protein, human TET1 protein, human transcription factor abdominal obesity adult apoptosis Article controlled study disease severity DNA methylation DNA modification epigenetics female gene dosage gene locus genetic susceptibility genetic variability histopathology human human tissue hypertension hypertriglyceridemia immunohistochemistry insulin resistance liver biopsy liver fibrosis liver histology liver mitochondrion major clinical study male middle aged mitochondrial genome next generation sequencing non insulin dependent diabetes mellitus nonalcoholic fatty liver observational study priority journal protein expression protein methylation single nucleotide polymorphism steatosis analogs and derivatives genetic epigenesis genetic predisposition genetics liver metabolism Non-alcoholic Fatty Liver Disease organelle biogenesis pathology Adult Cytosine DNA Methylation DNA-Binding Proteins Epigenesis, Genetic Female Genetic Predisposition to Disease Heat-Shock Proteins Humans Liver Male Middle Aged Mitochondria, Liver Non-alcoholic Fatty Liver Disease Organelle Biogenesis Proto-Oncogene Proteins Transcription Factors |
| description |
The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained. Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n=90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1-3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants. We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R=0.50, P=0.000382) and PPARGC1A-mRNA levels (R=-0.57, P=0.04). We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4-0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8-0.8), means-standard deviation, P=0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10-1.97; P=0.005). The p.Ile1762- Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and transcriptional levels, and Type 2 diabetes. Our results suggest that 5-hmC might be involved in the pathogenesis of NAFLD by regulating liver mitochondrial biogenesis and PPARGC1A expression. Genetic diversity at TET loci suggests an ''epigenetic'' regulation of programmed liver-cell death and a TETmediated fine-tuning of the liver PPARGC1A-transcriptional program. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. |
| title |
Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins |
| title_short |
Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins |
| title_full |
Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins |
| title_fullStr |
Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins |
| title_full_unstemmed |
Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins |
| title_sort |
epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of dna hydroxymethylation and tet proteins |
| publishDate |
2015 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257974_v94_n36_p_Pirola http://hdl.handle.net/20.500.12110/paper_00257974_v94_n36_p_Pirola |
| _version_ |
1768545635852615680 |
| spelling |
paper:paper_00257974_v94_n36_p_Pirola2023-06-08T14:53:42Z Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins 5 hydroxymethylcytosine cytokeratin 18 messenger RNA mitochondrial DNA peptides and proteins peroxisome proliferator activated receptor gamma coactivator 1alpha ten eleven translocation 1 protein ten eleven translocation 2 protein ten eleven translocation 3 protein unclassified drug 5-hydroxymethylcytosine cytosine DNA binding protein heat shock protein oncoprotein PPARGC1A protein, human TET1 protein, human transcription factor abdominal obesity adult apoptosis Article controlled study disease severity DNA methylation DNA modification epigenetics female gene dosage gene locus genetic susceptibility genetic variability histopathology human human tissue hypertension hypertriglyceridemia immunohistochemistry insulin resistance liver biopsy liver fibrosis liver histology liver mitochondrion major clinical study male middle aged mitochondrial genome next generation sequencing non insulin dependent diabetes mellitus nonalcoholic fatty liver observational study priority journal protein expression protein methylation single nucleotide polymorphism steatosis analogs and derivatives genetic epigenesis genetic predisposition genetics liver metabolism Non-alcoholic Fatty Liver Disease organelle biogenesis pathology Adult Cytosine DNA Methylation DNA-Binding Proteins Epigenesis, Genetic Female Genetic Predisposition to Disease Heat-Shock Proteins Humans Liver Male Middle Aged Mitochondria, Liver Non-alcoholic Fatty Liver Disease Organelle Biogenesis Proto-Oncogene Proteins Transcription Factors The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained. Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n=90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1-3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants. We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R=0.50, P=0.000382) and PPARGC1A-mRNA levels (R=-0.57, P=0.04). We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4-0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8-0.8), means-standard deviation, P=0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10-1.97; P=0.005). The p.Ile1762- Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and transcriptional levels, and Type 2 diabetes. Our results suggest that 5-hmC might be involved in the pathogenesis of NAFLD by regulating liver mitochondrial biogenesis and PPARGC1A expression. Genetic diversity at TET loci suggests an ''epigenetic'' regulation of programmed liver-cell death and a TETmediated fine-tuning of the liver PPARGC1A-transcriptional program. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257974_v94_n36_p_Pirola http://hdl.handle.net/20.500.12110/paper_00257974_v94_n36_p_Pirola |