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Abstract:

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.

Registro:

Documento: Artículo
Título:Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins
Autor:Pirola, C.J.; Scian, R.; Gianotti, T.F.; Dopazo, H.; Rohr, C.; Martino, J.S.; Castaño, G.O.; Sookoian, S.
Filiación:Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
Biomedical Genomics and Evolution Laboratory, Ecology, Genetics and Evolution Department, Faculty of Science, IEGEBA, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
Department of Pathology, Hospital Diego Thompson San Martin, Buenos Aires, Argentina
Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina
Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
Palabras clave: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
Año:2015
Volumen:94
Número:36
DOI: http://dx.doi.org/10.1097/MD.0000000000001480
Título revista:Medicine (United States)
Título revista abreviado:Medicine
ISSN:00257974
CODEN:MEDIA
CAS:5 hydroxymethylcytosine, 1123-95-1; cytosine, 71-30-7; 5-hydroxymethylcytosine; Cytosine; DNA-Binding Proteins; Heat-Shock Proteins; PPARGC1A protein, human; Proto-Oncogene Proteins; TET1 protein, human; Transcription Factors
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257974_v94_n36_p_Pirola

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Citas:

---------- APA ----------
Pirola, C.J., Scian, R., Gianotti, T.F., Dopazo, H., Rohr, C., Martino, J.S., Castaño, G.O.,..., Sookoian, S. (2015) . Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins. Medicine (United States), 94(36).
http://dx.doi.org/10.1097/MD.0000000000001480
---------- CHICAGO ----------
Pirola, C.J., Scian, R., Gianotti, T.F., Dopazo, H., Rohr, C., Martino, J.S., et al. "Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins" . Medicine (United States) 94, no. 36 (2015).
http://dx.doi.org/10.1097/MD.0000000000001480
---------- MLA ----------
Pirola, C.J., Scian, R., Gianotti, T.F., Dopazo, H., Rohr, C., Martino, J.S., et al. "Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins" . Medicine (United States), vol. 94, no. 36, 2015.
http://dx.doi.org/10.1097/MD.0000000000001480
---------- VANCOUVER ----------
Pirola, C.J., Scian, R., Gianotti, T.F., Dopazo, H., Rohr, C., Martino, J.S., et al. Epigenetic modifications in the biology of nonalcoholic fatty liver disease: The role of DNA hydroxymethylation and TET proteins. Medicine. 2015;94(36).
http://dx.doi.org/10.1097/MD.0000000000001480