2 DIFFERENT CIS-ACTING REGULATORY REGIONS DIRECT CELL-SPECIFIC TRANSCRIPTION OF THE COLLAGEN ALPHA(1)(I) GENE IN HEPATIC STELLATE CELLS ANDIN 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 t he 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 th at collagen alpha(1)(I)-human growth hormone transgene expression was constitutively high in tendon and skin, provided the transgene contain ed the -2.3 to -0.44 kb collagen regulatory region, However in the liv er, expression was stimulated several-fold, as was the endogeneous gen e, by the fibrogenic hepatotoxin carbon tetrachloride. This stimulatio n 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 in tron (+292 to +1607 bp), In addition, the -0.44 kb 5' region was suffi cient for high-level transgene expression in stellate cells, following their activation by culture on plastic, In contrast, in skin and tend on, 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-regu latory regions direct cell-specific transcription of the collagen alph a(1)(I) gene in stellate cells and in skin and tendon.