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(The FASEB Journal. 2000;14:95-102.)
© 2000 FASEB

Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation

LUIS TORRES*,1, MATÍAS A. ÁVILA*,1, M. VICTORIA CARRETERO*, M. UJUE LATASA*, JOAN CABALLERÍA{dagger}, GERARDO LÓPEZ-RODAS{ddagger}, ABDELHALIM BOUKABA{ddagger}, SHELLY C. LU§, LUIS FRANCO{ddagger} and JOSÉ M. MATO*2

* División de Hepatología y Terapia Génica, Departamento de Medicina Interna, Facultad de Medicina, Universidad de Navarra, 31008 Pamplona, Spain;
{dagger} Servicio de Hepatología, Hospital Clínico y Provincial, 08036 Barcelona, Spain;
{ddagger} Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, Burjassot, 46100 València, Spain; and
§ Center for Liver Disease Research and Division of Gastrointestinal Liver Diseases, Department of Medicine, University of Southern California School of Medicine, Los Angeles, California 90033, USA

2Correspondence: División de Hepatología y Terapia Génica, Departamento de Medicina Interna. Facultad de Medicina. Universidad de Navarra. 31008, Pamplona, Navarra, Spain. Tel: 34–948-425678. Fax: 34–948-425677. E-mail: jmmato{at}unav.es

Methionine adenosyltransferase (MAT) is the enzyme that catalyzes the synthesis of S-adenosylmethionine (AdoMet), the main donor of methyl groups in the cell. In mammals MAT is the product of two genes, MAT1A and MAT2A. MAT1A is expressed only in the mature liver whereas fetal hepatocytes, extrahepatic tissues and liver cancer cells express MAT2A. The mechanisms behind the tissue and differentiation state specific MAT1A expression are not known. In the present work we examined MAT1A promoter methylation status by means of methylation sensitive restriction enzyme analysis. Our data indicate that MAT1A promoter is hypomethylated in liver and hypermethylated in kidney and fetal rat hepatocytes, indicating that this modification is tissue specific and developmentally regulated. Immunoprecipitation of mononucleosomes from liver and kidney tissues with antibodies mainly specific to acetylated histone H4 and subsequent Southern blot analysis with a MAT1A promoter probe demonstrated that MAT1A expression is linked to elevated levels of chromatin acetylation. Early changes in MAT1A methylation are already observed in the precancerous cirrhotic livers from rats, which show reduced MAT1A expression. Human hepatoma cell lines in which MAT1A is not expressed were also hypermethylated at this locus. Finally we demonstrate that MAT1A expression is reactivated in the human hepatoma cell line HepG2 treated with 5-aza-2'-deoxycytidine or the histone deacetylase inhibitor trichostatin, suggesting a role for DNA hypermethylation and histone deacetylation in MAT1A silencing.—Torres, L., Ávila, M. A., Carretero, M. V., Latasa, M. U., Caballería, J., López-Rodas, G., Boukaba, A., Lu, S. C., Franco, L., Mato, J. M. Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation.


Key Words: S-adenosylmethionine synthesis • DNA methylation • tissue-specific expression • liver cirrhosis • hepatocarcinoma




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