2 DIFFERENT CIS-ACTING REGULATORY REGIONS DIRECT CELL-SPECIFIC TRANSCRIPTION OF THE COLLAGEN ALPHA(1)(I) GENE IN HEPATIC STELLATE CELLS AND IN SKIN AND TENDON FIBROBLASTS

The expression of the collagen alpha(1)(I) gene in activated stellate cells plays an important role during liver fibrogenesis. To identify the critical cis-elements of the collagen alpha(1)(I) gene in stellate cells, we used transgenic animals bearing various collagen alpha(1)(I) regulatory regions directing the expression of either a human growth hormone minigene or the bacterial beta-galactosidase gene, We found that collagen alpha(1)(I)-human growth hormone transgene expression was constitutively high in tendon and skin, provided the transgene contained the -2.3 to -0.44 kb collagen regulatory region, However in the liver, expression was stimulated several-fold, as was the endogeneous gene, by the fibrogenic hepatotoxin carbon tetrachloride. This stimulation occurred whether the collagen 5' regulatory region extended -2.3, -1.6 or -0.44 kb, and in the presence or absence of much of the first intron (+292 to +1607 bp), In addition, the -0.44 kb 5' region was sufficient for high-level transgene expression in stellate cells, following their activation by culture on plastic, In contrast, in skin and tendon, high-level transcription of the collagen alpha(1)(I) gene required the -2.3 to -0.44 kb 5' flanking region, Thus, two different cis-regulatory regions direct cell-specific transcription of the collagen alpha(1)(I) gene in stellate cells and in skin and tendon.