Fibrinogen gene regulation

Summary

The Aα, Bβ and γ polypeptide chains of fibrinogen are encoded by a three gene cluster on human chromosome four. The fibrinogen genes (FGB-FGA-FGG) are expressed almost exclusively in hepatocytes where their output is coordinated to ensure a sufficient mRNA pool for each chain and maintain an abundant plasma fibrinogen protein level. Fibrinogen gene expression is controlled by the activity of proximal promoters which contain binding sites for hepatocyte transcription factors, including proteins which influence fibrinogen transcription in response to acute-phase inflammatory stimuli. The fibrinogen gene cluster also contains cis regulatory elements; enhancer sequences with liver activities identified by sequence conservation and functional genomics. While the transcriptional control of this gene cluster is fascinating biology, the medical impetus to understand fibrinogen gene regulation stems from the association of cardiovascular disease risk with high level circulating fibrinogen. In the general population this level varies from about 1.5 to 3.5 g/l. This variation between individuals is influenced by genotype, suggesting there are genetic variants contributing to fibrinogen levels which reside in fibrinogen regulatory loci. A complete picture of how fibrinogen genes are regulated will therefore point towards novel sources of regulatory variants. In this review we discuss regulation of the fibrinogen genes from proximal promoters and enhancers, the influence of acute-phase stimulation, post-transcriptional regulation by miRNAs and functional regulatory variants identified in genetic studies. Finally, we discuss the fibrinogen locus in light of recent advances in understanding chromosomal architecture and suggest future directions for researching the mechanisms that control fibrinogen expression.

Keywords

Fibrinogen - gene regulation - promoter - enhancer - miRNA

• References

• 1 Doolittle RF. Fibrinogen and fibrin. Annu Rev Biochem 1984; 53: 195-229.
• 2 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 03: 1894-1904.
• 3 Standeven KF, Ariens RA, Grant PJ. The molecular physiology and pathology of fibrin structure/function. Blood Rev 2005; 19: 275-288.
• 4 Sahni A, Francis CW. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation. Blood 2000; 96: 3772-3778.
• 5 Sahni A, Odrljin T, Francis CW. Binding of basic fibroblast growth factor to fibrinogen and fibrin. J Biol Chem 1998; 273: 7554-7559.
• 6 Clark RA, Lanigan JM, DellaPelle P. et al. Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol 1982; 79: 264-269.
• 7 Donaldson DJ, Mahan JT, Amrani D. et al. Fibrinogen-mediated epidermal cell migration: structural correlates for fibrinogen function. J Cell Sci 1989; 94: 101-108.
• 8 Kant JA, Fornace Jr AJ, Saxe D. et al. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci USA 1985; 82: 2344-2348.
• 9 de Moerloose P, Boehlen F, Neerman-Arbez M. Fibrinogen and the risk of thrombosis. Semin Thromb Hemost 2010; 36: 7-17.
• 10 de Moerloose P, Neerman-Arbez M. Congenital fibrinogen disorders. Semin Thromb Hemost 2009; 35: 356-366.
• 11 Danesh J, Collins R, Appleby P. et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. J Am Med Assoc 1998; 279: 1477-1482.
• 12 Danesh J, Lewington S, Thompson SG. et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
• 13 Lowe GD, Rumley A. Fibrinogen and its degradation products as thrombotic risk factors. Ann NY Acad Sci 2001; 936: 560-565.
• 14 Kaptoge S, White IR, Thompson SG. et al. Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration. Am J Epidemiol 2007; 166: 867-879.
• 15 Woodward M, Rumley A, Welsh P. et al. A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease. J Thromb Haemost 2007; 05: 1795-1800.
• 16 Welsh P, Woodward M, Rumley A. et al. Associations of plasma pro-inflammatory cytokines, fibrinogen, viscosity and C-reactive protein with cardiovascular risk factors and social deprivation: the fourth Glasgow MONICA study. Br J Haematol 2008; 141: 852-861.
• 17 Kamphuisen PW, Eikenboom JC, Vos HL. et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999; 81: 680-683.
• 18 Machlus KR, Cardenas JC, Church FC. et al. Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice. Blood 2011; 117: 4953-4963.
• 19 Green FR. Fibrinogen polymorphisms and atherothrombotic disease. Ann NY Acad Sci 2001; 936: 549-559.
• 20 Crabtree GR, Kant JA. Molecular cloning of cDNA for the alpha, beta, and gamma chains of rat fibrinogen. A family of coordinately regulated genes. J Biol Chem 1981; 256: 9718-9723.
• 21 Crabtree GR, Kant JA. Coordinate accumulation of the mRNAs for the alpha, beta, and gamma chains of rat fibrinogen following defibrination. J Biol Chem 1982; 257: 7277-7279.
• 22 Grieninger G, Hertzberg KM, Pindyck J. Fibrinogen synthesis in serum-free hepatocyte cultures: stimulation by glucocorticoids. Proc Natl Acad Sci USA 1978; 75: 5506-5510.
• 23 Fuller GM, Otto JM, Woloski BM. et al. The effects of hepatocyte stimulating factor on fibrinogen biosynthesis in hepatocyte monolayers. J Cell Biol 1985; 101: 1481-1486.
• 24 Ritchie DG, Fuller GM. Hepatocyte-stimulating factor: a monocyte-derived acute-phase regulatory protein. Ann NY Acad Sci 1983; 408: 490-502.
• 25 Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340: 448-454.
• 26 Fuller GM, Zhang Z. Transcriptional control mechanism of fibrinogen gene expression. Ann NY Acad Sci 2001; 936: 469-479.
• 27 Courtois G, Morgan JG, Campbell LA. et al. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters. Science 1987; 238: 688-692.
• 28 Hu CH, Harris JE, Davie EW. et al. Characterization of the 5'-flanking region of the gene for the alpha chain of human fibrinogen. J Biol Chem 1995; 270: 28342-28349.
• 29 Dalmon J, Laurent M, Courtois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. Mol Cell Biol 1993; 13: 1183-1193.
• 30 Mizuguchi J, Hu CH, Cao Z. et al. Characterization of the 5'-flanking region of the gene for the gamma chain of human fibrinogen. J Biol Chem 1995; 270: 28350-28356.
• 31 Morgan JG, Courtois G, Fourel G. et al. Sp1, a CAAT-binding factor, and the adenovirus major late promoter transcription factor interact with functional regions of the gamma-fibrinogen promoter. Mol Cell Biol 1988; 08: 2628-2637.
• 32 Huber P, Laurent M, Dalmon J. Human beta-fibrinogen gene expression. Upstream sequences involved in its tissue specific expression and its dexamethasone and interleukin 6 stimulation. J Biol Chem 1990; 265: 5695-5701.
• 33 Anderson GM, Shaw AR, Shafer JA. Functional characterization of promoter elements involved in regulation of human B beta-fibrinogen expression. Evidence for binding of novel activator and repressor proteins. J Biol Chem 1993; 268: 22650-2265.
• 34 Zhang Z, Fuentes NL, Fuller GM. Characterization of the IL-6 responsive elements in the gamma fibrinogen gene promoter. J Biol Chem 1995; 270: 24287-24291.
• 35 Liu Z, Fuller GM. Detection of a novel transcription factor for the A alpha fibrinogen gene in response to interleukin-6. J Biol Chem 1995; 270: 7580-7586.
• 36 Liu Z, Fuentes NL, Jones SA. et al. A unique transcription factor for the A alpha fibrinogen gene is related to the mitochondrial single-stranded DNA binding protein P16. Biochemistry 1997; 36: 14799-14806.
• 37 Zhang Z, Fuller GM. Interleukin 1beta inhibits interleukin 6-mediated rat gamma fibrinogen gene expression. Blood 2000; 96: 3466-3472.
• 38 Albrecht U, Yang X, Asselta R. et al. Activation of NF-kappaB by IL-1beta blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human gamma-fibrinogen gene. Cell Signal 2007; 19: 1866-1878.
• 39 Otto JM, Grenett HE, Fuller GM. The coordinated regulation of fibrinogen gene transcription by hepatocyte-stimulating factor and dexamethasone. J Cell Biol 1987; 105: 1067-1072.
• 40 Zhang Z, Jones S, Hagood JS. et al. STAT3 acts as a co-activator of glucocorticoid receptor signaling. J Biol Chem 1997; 272: 30607-30610.
• 41 Asselta R, Duga S, Modugno M. et al. Identification of a glucocorticoid response element in the human gamma chain fibrinogen promoter. Thromb Haemost 1998; 79: 1144-1150.
• 42 Dittrich A, Khouri C, Sackett SD. et al. Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor. Hepatology 2012; 55: 256-266.
• 43 Fowlkes DM, Mullis NT, Comeau CM. et al. Potential basis for regulation of the coordinately expressed fibrinogen genes: homology in the 5' flanking regions. Proc Natl Acad Sci USA 1984; 81: 2313-2316.
• 44 Huber P, Dalmon J, Courtois G. et al. Characterization of the 5'-flanking region for the human fibrinogen beta gene. Nucleic Acids Res 1987; 15: 1615-1625.
• 45 Roy S, Overton O, Redman C. Overexpression of any fibrinogen chain by Hep G2 cells specifically elevates the expression of the other two chains. J Biol Chem 1994; 269: 691-695.
• 46 Roy SN, Mukhopadhyay G, Redman CM. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen. J Biol Chem 1990; 265: 6389-6393.
• 47 Rezaee F, Maas A, Verheijen JH. et al. Increased hepatic fibrinogen Bbeta-gene transcription is not enough to increase plasma fibrinogen levels. A transgenic mouse study. Thromb Haemost 2001; 85: 1025-1030.
• 48 Suh TT, Holmback K, Jensen NJ. et al. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995; 09: 2020-2033.
• 49 Bremner WF, Sothern RB, Kanabrocki EL. et al. Relation between circadian patterns in levels of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men. Am Heart J 2000; 139: 164-173.
• 50 Sakao E, Ishihara A, Horikawa K. et al. Two-peaked synchronization in day/night expression rhythms of the fibrinogen gene cluster in the mouse liver. J Biol Chem 2003; 278: 30450-30457.
• 51 Ahituv N, Prabhakar S, Poulin F. et al. Mapping cis-regulatory domains in the human genome using multi-species conservation of synteny. Hum Mol Genet 2005; 14: 3057-3063.
• 52 Dermitzakis ET, Reymond A, Antonarakis SE. Conserved non-genic sequences - an unexpected feature of mammalian genomes. Nat Rev Genet 2005; 06: 151-157.
• 53 Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M. et al. In vivo enhancer analysis of human conserved non-coding sequences. Nature 2006; 444: 499-502.
• 54 Fort A, Fish RJ, Attanasio C. et al. A liver enhancer in the fibrinogen gene cluster. Blood 2011; 117: 276-282.
• 55 Schmidt D, Wilson MD, Ballester B. et al. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 2010; 328: 1036-1040.
• 56 Kuo CJ, Conley PB, Chen L. et al. A transcriptional hierarchy involved in mammalian cell-type specification. Nature 1992; 355: 457-461.
• 57 Birney E, Stamatoyannopoulos JA, Dutta A. et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799-816.
• 58 Visel A, Blow MJ, Li Z. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 2009; 457: 854-858.
• 59 Kasper LH, Fukuyama T, Biesen MA. et al. Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development. Mol Cell Biol 2006; 26: 789-809.
• 60 Vo N, Goodman RH. CREB-binding protein and p300 in transcriptional regulation. J Biol Chem 2001; 276: 13505-13508.
• 61 Ban N, Yamada Y, Someya Y. et al. Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter. Diabetes 2002; 51: 1409-1418.
• 62 Erickson RL, Hemati N, Ross SE. et al. p300 coactivates the adipogenic transcription factor CCAAT/enhancer-binding protein alpha. J Biol Chem 2001; 276: 16348-16355.
• 63 Mink S, Haenig B, Klempnauer KH. Interaction and functional collaboration of p300 and C/EBPbeta. Mol Cell Biol 1997; 17: 6609-6617.
• 64 Nakashima K, Yanagisawa M, Arakawa H. et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 1999; 284: 479-482.
• 65 Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215-233.
• 66 Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 2011; 12: 99-110.
• 67 Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010; 11: 597-610.
• 68 Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011 39. Database issue D152-157.
• 69 Fort A, Borel C, Migliavacca E. et al. Regulation of fibrinogen production by microRNAs. Blood 2010; 116: 2608-2615.
• 70 Hatziapostolou M, Polytarchou C, Aggelidou E. et al. An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 2011; 147: 1233-1247.
• 71 Brock M, Trenkmann M, Gay RE. et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-micro R-NA cluster 17/92 pathway. Circ Res 2009; 104: 1184-1191.
• 72 Brock M, Trenkmann M, Gay RE. et al. MicroRNA-18a enhances the interleukin-6-mediated production of the acute-phase proteins fibrinogen and haptoglobin in human hepatocytes. J Biol Chem 2011; 286: 40142-40150.
• 73 Reiner AP, Carty CL, Carlson CS. et al. Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study. J Thromb Haemost 2006; 04: 1279-1287.
• 74 Danik JS, Pare G, Chasman DI. et al. Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study. Circ Cardiovasc Genet 2009; 02: 134-141.
• 75 Dehghan A, Yang Q, Peters A. et al. Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. Circ Cardiovasc Genet 2009; 02: 125-133.
• 76 Thomas A, Lamlum H, Humphries S. et al. Linkage disequilibrium across the fi-brinogen locus as shown by five genetic polymorphisms, G/A-455 (HaeIII), C/T-148 (HindIII/AluI), T/G+1689 (AvaII), and BclI (beta-fibrinogen) and TaqI (alpha-fibrinogen), and their detection by PCR. Hum Mutat 1994; 03: 79-81.
• 77 de Maat MP, Kastelein JJ, Jukema JW. et al. -455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb Vasc Biol 1998; 18: 265-271.
• 78 Green F, Hamsten A, Blomback M. et al. The role of beta-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemost 1993; 70: 915-920.
• 79 Thomas AE, Green FR, Kelleher CH. et al. Variation in the promoter region of the beta fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-490.
• 80 van 't Hooft FM, von Bahr SJ, Silveira A. et al. Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol 1999; 19: 3063-3070.
• 81 Brown ET, Fuller GM. Detection of a complex that associates with the Bbeta fibrinogen G-455-A polymorphism. Blood 1998; 92: 3286-3293.
• 82 Verschuur M, de Jong M, Felida L. et al. A hepatocyte nuclear factor-3 site in the fibrinogen beta promoter is important for interleukin 6-induced expression, and its activity is influenced by the adjacent -148C/T polymorphism. J Biol Chem 2005; 280: 16763-16771.
• 83 de Wit E, de Laat W. A decade of 3C technologies: insights into nuclear organization. Genes Dev 2012; 26: 11-24.
• 84 Dekker J, Rippe K, Dekker M. et al. Capturing chromosome conformation. Science 2002; 295: 1306-1311.
• 85 Li G, Ruan X, Auerbach RK. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 2012; 148: 84-98.
• 86 Cook PR. The organization of replication and transcription. Science 1999; 284: 1790-1795.
• 87 Kim TK, Hemberg M, Gray JM. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 2010; 465: 182-187.
• 88 Birnbaum RY, Clowney EJ, Agamy O. et al. Coding exons function as tissue-specific enhancers of nearby genes. Genome Res. 2012 epub ahead of print.
• 89 Fish RJ, Neerman-Arbez M. A novel regulatory element between the human FGA and FGG genes. Thromb Haemost 2012; 108: 427-434.