Nitsch, Doris; Boshart, Michael; Schütz, Günther
Extinction of tyrosine aminotransferase gene activity in somatic cell hybrids involves modification and loss of several essential transcription factors.
In: Genes and Development, Vol. 7: pp. 308-319
Extinction is defined as the loss of cell type-specific gene expression that occurs in somatic cell hybrids
derived by fusion of cells with dissimilar phenotypes. To explore the basis of this dominant-negative
regulation, we have studied the activities of the control elements of the liver-specific gene encoding tyrosine
aminotransferase (TAT) in hepatoma/fibroblast hybrid crosses. We show that extinction in complete somatic
cell hybrids is accompanied by the loss of activity of all known cell type-specific control elements of the TAT
gene. This inactivity is the result of first, lack of expression of genes coding for the transcriptional activators
HNF4 and HNF3[~ and HNF33,, which bind to essential elements of the enhancers; and second, loss of in vivo
binding and activity of ubiquitous factors to these enhancers, including CREB, which is the target for
repression by the tissue-specific extinguisher locus TSE1. Complete extinction of TAT gene activity is
therefore a multifactorial process affecting all three enhancers controlling liver-specific and hormone-inducible
expression. It results from lack of activation, rather than active repression, and involves both
post-translational modification and loss of essential transcriptional activators.