Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins
- Autores
- Pirola, Carlos José; Scian, Romina; Fernández Gianotti, Tomás; Dopazo, Hernán Javier; Rohr, Cristian Oscar; San Martino, Julio; Castaño, Gustavo Osvaldo; Sookoian, Silvia Cristina
- Año de publicación
- 2015
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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.Ile1762Val 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 TET-mediated fine-tuning of the liver PPARGC1A-transcriptional program.
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Scian, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
Fil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
Fil: San Martino, Julio. Provincia de Buenos Aires. Ministerio de Salud. Hospital Municipal Dr. Diego Thompson; Argentina
Fil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina - Materia
-
Nafld
5hydroxymethyl-Citosine
Epigenetics
Tets
Genetics - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/39085
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Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET ProteinsPirola, Carlos JoséScian, RominaFernández Gianotti, TomásDopazo, Hernán JavierRohr, Cristian OscarSan Martino, JulioCastaño, Gustavo OsvaldoSookoian, Silvia CristinaNafld5hydroxymethyl-CitosineEpigeneticsTetsGeneticshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The 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.Ile1762Val 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 TET-mediated fine-tuning of the liver PPARGC1A-transcriptional program.Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Scian, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: San Martino, Julio. Provincia de Buenos Aires. Ministerio de Salud. Hospital Municipal Dr. Diego Thompson; ArgentinaFil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaLippincott Williams2015-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/39085Pirola, Carlos José; Scian, Romina; Fernández Gianotti, Tomás; Dopazo, Hernán Javier; Rohr, Cristian Oscar; et al.; Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins; Lippincott Williams; Medicine; 94; 36; 9-2015; 1480-14900025-7974CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1097/MD.0000000000001480info:eu-repo/semantics/altIdentifier/url/https://journals.lww.com/md-journal/Fulltext/2015/09020/Epigenetic_Modifications_in_the_Biology_of.24.aspxinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:49:31Zoai:ri.conicet.gov.ar:11336/39085instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:49:31.667CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins |
title |
Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins |
spellingShingle |
Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins Pirola, Carlos José Nafld 5hydroxymethyl-Citosine Epigenetics Tets Genetics |
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 |
dc.creator.none.fl_str_mv |
Pirola, Carlos José Scian, Romina Fernández Gianotti, Tomás Dopazo, Hernán Javier Rohr, Cristian Oscar San Martino, Julio Castaño, Gustavo Osvaldo Sookoian, Silvia Cristina |
author |
Pirola, Carlos José |
author_facet |
Pirola, Carlos José Scian, Romina Fernández Gianotti, Tomás Dopazo, Hernán Javier Rohr, Cristian Oscar San Martino, Julio Castaño, Gustavo Osvaldo Sookoian, Silvia Cristina |
author_role |
author |
author2 |
Scian, Romina Fernández Gianotti, Tomás Dopazo, Hernán Javier Rohr, Cristian Oscar San Martino, Julio Castaño, Gustavo Osvaldo Sookoian, Silvia Cristina |
author2_role |
author author author author author author author |
dc.subject.none.fl_str_mv |
Nafld 5hydroxymethyl-Citosine Epigenetics Tets Genetics |
topic |
Nafld 5hydroxymethyl-Citosine Epigenetics Tets Genetics |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
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.Ile1762Val 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 TET-mediated fine-tuning of the liver PPARGC1A-transcriptional program. Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Scian, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina Fil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina Fil: San Martino, Julio. Provincia de Buenos Aires. Ministerio de Salud. Hospital Municipal Dr. Diego Thompson; Argentina Fil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina |
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.Ile1762Val 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 TET-mediated fine-tuning of the liver PPARGC1A-transcriptional program. |
publishDate |
2015 |
dc.date.none.fl_str_mv |
2015-09 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/39085 Pirola, Carlos José; Scian, Romina; Fernández Gianotti, Tomás; Dopazo, Hernán Javier; Rohr, Cristian Oscar; et al.; Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins; Lippincott Williams; Medicine; 94; 36; 9-2015; 1480-1490 0025-7974 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/39085 |
identifier_str_mv |
Pirola, Carlos José; Scian, Romina; Fernández Gianotti, Tomás; Dopazo, Hernán Javier; Rohr, Cristian Oscar; et al.; Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins; Lippincott Williams; Medicine; 94; 36; 9-2015; 1480-1490 0025-7974 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1097/MD.0000000000001480 info:eu-repo/semantics/altIdentifier/url/https://journals.lww.com/md-journal/Fulltext/2015/09020/Epigenetic_Modifications_in_the_Biology_of.24.aspx |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Lippincott Williams |
publisher.none.fl_str_mv |
Lippincott Williams |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.070432 |