Potential basis for regulation of the coordinately expressed fibrinogen genes: homology in the 5' flanking regions

Abstract

The three chains of fibrinogen are encoded by three separate genes whose transcription is coordinately regulated. The breakdown of fibrinogen during the acute-phase reaction leads to a simultaneous increase in alpha-, beta-, and gamma-fibrinogen mRNA in the liver. In a search for the basis of this coordinate increase in transcription, we have determined the sequences of the regions surrounding the points of transcriptional initiation of the three rat fibrinogen genes, 1490 nucleotides upstream and 730 nucleotides downstream. Two unique regions of homology have been found. One region consists of 15 nucleotides that have a common 6-nucleotide core lying between -116 and -160; the other is approximately equal to 100 nucleotides long and is in the -165 to -472 region. In this region, the beta- and gamma-fibrinogen genes are approximately equal to 65% homologous. alpha-Fibrinogen has somewhat less homology with both beta- and gamma-fibrinogen. In addition, the beta-fibrinogen gene has 22 nucleotides at position -480 that are homologous to sequences that have been noted to occur in glucocorticosteroid-regulated genes in a similar position. We feel that these areas of conserved sequences play a role in the regulation of the transcription of fibrinogen. The fibrinogen chains are synthesized as precursor peptides, and the amino-terminal portion, the so-called signal peptide, is removed during the translocation of the peptide chain across the endoplasmic reticulum. We have determined those sequences that encode the signal peptides. Homology in the amino acid sequence between the rat and human signal peptides varies between 52% for alpha-fibrinogen and 66% for beta-fibrinogen. This homology implies that there has been strong selective pressure on this portion of these genes.