Activation of tyrosine aminotransferase expression in hepatic differentiation

Elucidation of those molecular mechanisms regulating development and differentiation is a central question of contemporary biology and biochemistry. The developmental activation of the liver-specific enzyme tyrosine aminotransferase (L-tyrosine: 2-oxoglutarate arainotransferase, E.G. 2.6.1.5, TAT) has been qualitatively described in terms of the appearance of functional gene products and the role of effector molecules. The underlying developmental events to account for this activation have yet to be identified. It was the purpose of this investigation to analyze the activity of the aminotransferase gene during development. The project had two major areas of research. One involved the titration of hybridizable transcripts in perinatal rat liver using a cloned cDNA specific for messenger RNA^TAT (mRNA^TAT) sequences. The other used treatment of fetuses in utero with a potent inhibitor of DNA methylation, 5-azacytidine (5-azaC) to test whether the extent of specific. DNA raethylations could be implicated in the developmental activation of this gene. We present evidence here that supports our hypothesis that the rapid appearance of gene products in neonates is the consequence of an increased number of mRNA^TAT sequences. The data also suggest that the ability of those transcripts to be expressed is regulated posttranscriptionally, probably at the level of translation. Treatment of fetuses in utero with 5-azaC activated the expression of aminotransferase gene products in a pattern not unlike that seen in the course of normal development. In addition, 5-azaC treatment induced changes in hepatic morphology and metabolism, apparently accelerating the developmental process. From these studies we conclude that the activation of tyrosine aminotransferase expression is probably the consequence of an increased rate of aminotransferase transcription. Superimposed on this is some form of post-transcrlptional control which limits temporarily the capacity of the gene transcripts to be translated. Furthermore, we conclude that 5-azaC treatment in utero accelerates hepatic differentiation. The specific effect of this drug on TAT activation could be either on the structural gene itself or those hypothetical regulatory loci required for fully differentiated enzyme expression.