Methylation of the regulatory region of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene leads to its transcriptional inactivation.

The mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene is expressed in a limited set of tissues in the adult rat. Methylation of the 5' flanking region of the gene in vitro leads to its transcriptional inactivation when transfected in hepatoma-derived cell lines. In liver and kidney, expression of the gene correlates inversely with its degree of methylation, indicating that the methylation of the 5' flanking region and the first exon of the gene may be one of the factors responsible for the repression of its transcription. During the fetal/neonatal transition, a process of selective undermethylation of specific sites takes place in the 5' flanking region of the mitochondrial HMG-CoA synthase gene. Moreover, treatment with the hypomethylating agent 5-azacytidine of a hepatoma-derived cell line that presents barely detectable levels of mitochondrial HMG-CoA synthase mRNA leads to a significant increase in the mRNA levels. These results point to methylation as one of the regulatory mechanisms that operate on the mitochondrial HMG-CoA synthase gene.