Developmental control of argininosuccinate lyase gene by methylation.

The gene of argininosuccinate lyase (ASL) is expressed in a developmental specific manner in the liver and is regulated by hormones, namely glucocorticoids, glucagon and insulin. To assess the role of DNA methylation in the developmental pattern of ASL gene expression, we analyzed the restriction profile obtained by cleavage of genomic DNA with MspI and HpaII in fetal and adult rat liver, two developmental stages with different levels of expression of the ASL gene. Southern analysis showed that the 5' region of this gene appeared more methylated in the fetal liver which expressed ASL at a low level than in the adult liver where the ASL gene is highly expressed. Moreover, treatment of fetuses of various gestational stages with the hypomethylating agent 5-azacytidine for 18 h caused an increase of the hepatic ASL activity and mRNA level. The stimulating effect of this drug could be also observed in vitro in cultured fetal hepatocytes. These results suggest a developmental control of the ASL gene by the DNA methylation status.