Fatty acid desaturases (FADS) play an important role in the formation of omega-6 and omega-3 highly unsaturated fatty acids (HUFAs). The composition of HUFAs in the human metabolome is important for membrane fluidity and for the modulation of essential physiological functions such as inflammation processes and brain development. Several recent studies reported significant associations of single nucleotide polymorphisms (SNPs) in the human FADS gene cluster with HUFA levels and composition. The presence of the minor allele correlated with a decrease of desaturase reaction products and an accumulation of substrates. We performed functional studies with two of the associated polymorphisms (rs3834458 and rs968567) and showed an influence of polymorphism rs968567 on FADS2 promoter activity by luciferase reporter gene assays. Electrophoretic mobility shift assays proved allele-dependent DNA-binding ability of at least two protein complexes to the region containing SNP rs968567. One of the proteins binding to this region in an allele-specific manner was shown to be the transcription factor ELK1 (a member of ETS domain transcription factor family). These results indicate that rs968567 influences FADS2 transcription and offer first insights into the modulation of complex regulation mechanisms of FADS2 gene transcription by SNPs. Fatty acid desaturases (FADS) play an important role in the formation of omega-6 and omega-3 highly unsaturated fatty acids (HUFAs). The composition of HUFAs in the human metabolome is important for membrane fluidity and for the modulation of essential physiological functions such as inflammation processes and brain development. Several recent studies reported significant associations of single nucleotide polymorphisms (SNPs) in the human FADS gene cluster with HUFA levels and composition. The presence of the minor allele correlated with a decrease of desaturase reaction products and an accumulation of substrates. We performed functional studies with two of the associated polymorphisms (rs3834458 and rs968567) and showed an influence of polymorphism rs968567 on FADS2 promoter activity by luciferase reporter gene assays. Electrophoretic mobility shift assays proved allele-dependent DNA-binding ability of at least two protein complexes to the region containing SNP rs968567. One of the proteins binding to this region in an allele-specific manner was shown to be the transcription factor ELK1 (a member of ETS domain transcription factor family). These results indicate that rs968567 influences FADS2 transcription and offer first insights into the modulation of complex regulation mechanisms of FADS2 gene transcription by SNPs. Fatty acids are among other metabolites essential components of the human metabolome. In cells, phospholipids containing highly unsaturated fatty acids (HUFAs) such as arachidonic acid (all-cis-5,8,11,14-eicosatetraenoic acid or C20:4n-6) and docosahexaenoic acid [22:6(ω-3), all-cis-docosa-4,7,10,13,16,19-hexaenoic acid or C22:6n-3] have a positive effect on the fluidity of cell membranes. On the molecular level, HUFAs fulfill several other central functions like acting as second messengers in intracellular signaling pathways or regulating transcription. On the physiological level, HUFAs are important for brain development, acquisition of cognitive behaviors, and development of visual functions in early life. In addition, HUFAs are precursors for eicosanoids (leukotriens and prostaglandins), which play an important role in inflammatory processes (1Nakamura M.T. Nara T.Y. Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases.Annu. Rev. Nutr. 2004; 24: 345-376Crossref PubMed Scopus (837) Google Scholar). The production of HUFAs from dietary fatty acids includes several desaturation and elongation steps. The desaturases involved in this reaction cascade, delta-6 desaturase and delta-5 desaturase, are the rate-limiting enzymes. Both are expressed in the majority of human tissues, with highest levels in liver and to a smaller amount in brain, heart, and lung (2Cho H.P. Nakamura M. Clarke S.D. Cloning, expression, and fatty acid regulation of the human delta-5 desaturase.J. Biol. Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar, 3Cho H.P. Nakamura M.T. Clarke S.D. Cloning, expression, and nutritional regulation of the mammalian Delta-6 desaturase.J. Biol. Chem. 1999; 274: 471-477Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar). Delta-6 desaturase inserts a double bond at position 6 and after an elongation step, delta-5 desaturase inserts an additional double bond at position 5 of the elongated fatty acid chain. These conversions result in the formation of either arachidonic acid (C20:4n-6) in the omega-6 pathway or of eicosapentaenoic acid (C20:5n-3) in the omega-3 pathway. These molecules are either converted into eicosanoids or further elongated and desaturated, again with the help of the delta-6 desaturase (1Nakamura M.T. Nara T.Y. Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases.Annu. Rev. Nutr. 2004; 24: 345-376Crossref PubMed Scopus (837) Google Scholar). The importance of delta-6 desaturase for the formation of HUFAs and their influence on membrane integrity and fluidity was shown in a recent study by Stoffel et al. (4Stoffel W. Holz B. Jenke B. Binczek E. Gunter R.H. Kiss C. Karakesisoglou I. Thevis M. Weber A.A. Arnhold S. et al.Delta6-desaturase (FADS2) deficiency unveils the role of omega3- and omega6-polyunsaturated fatty acids.EMBO J. 2008; 27: 2281-2292Crossref PubMed Scopus (174) Google Scholar) who generated a fads2 −/− (fatty acid desaturase) mouse. In this animal model, membrane polarity of Sertoli and ovarian follicle cells was completely disturbed due to the lack of HUFAs in knockout mice caused by the delta-6 desaturase deficiency. Furthermore, both male and female mice were infertile and eicosanoid synthesis was disturbed. However, the administration of a HUFA-rich diet (either C20:4n-6 or C20:5n-3/C22:6n-3) enabled the fads2 −/− mice to overcome the genetic defect, restored the fatty acid pattern in membrane lipids, and rescued spermatogenesis as well as normal follicle development. Similarly, eicosanoid synthesis was restored by administration of arachidonic acid. Similar effects were observed in another fads2 −/− mouse by Stroud et al. (5Stroud C.K. Nara T.Y. Roqueta-Rivera M. Radlowski E.C. Lawrence P. Zhang Y. Cho B.H. Segre M. Hess R.A. Brenna J.T. et al.Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration.J Lipid Res. 2009; (Epub ahead of print. April 7, 2009.)Abstract Full Text Full Text PDF Scopus (126) Google Scholar). These studies showed that the level and composition of HUFAs in the body highly depends on the conversion rate of the delta-6 desaturase, which is in turn regulated by supply with dietary fatty acids and hormone signaling. The effect of dietary fatty acids on desaturase transcription regulation is mediated by two transcription factors, sterol regulatory element binding protein (SREBP1) and peroxisome proliferator activated receptor (PPARA) (6Matsuzaka T. Shimano H. Yahagi N. Amemiya-Kudo M. Yoshikawa T. Hasty A.H. Tamura Y. Osuga J. Okazaki H. Iizuka Y. et al.Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expression by SREBP-1 and PPARalpha.J. Lipid Res. 2002; 43: 107-114Abstract Full Text Full Text PDF PubMed Google Scholar). The feedback regulation mechanisms by which dietary fatty acids act on SREBP1 processing and stability, which in turn influence FADS2 gene expression, have been investigated intensively (7Hannah V.C. Ou J. Luong A. Goldstein J.L. Brown M.S. Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells.J. Biol. Chem. 2001; 276: 4365-4372Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 8Mater M.K. Thelen A.P. Pan D.A. Jump D.B. Sterol response element-binding protein 1c (SREBP1c) is involved in the polyunsaturated fatty acid suppression of hepatic S14 gene transcription.J. Biol. Chem. 1999; 274: 32725-32732Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 9Xu J. Nakamura M.T. Cho H.P. Clarke S.D. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats.J. Biol. Chem. 1999; 274: 23577-23583Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 10Xu J. Teran-Garcia M. Park J.H. Nakamura M.T. Clarke S.D. Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay.J. Biol. Chem. 2001; 276: 9800-9807Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 11Yoshikawa T. Shimano H. Yahagi N. Ide T. Amemiya-Kudo M. Matsuzaka T. Nakakuki M. Tomita S. Okazaki H. Tamura Y. et al.Polyunsaturated fatty acids suppress sterol regulatory element-binding protein 1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements.J. Biol. Chem. 2002; 277: 1705-1711Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). The induction of desaturases by PPARA was shown to occur both by indirect and direct mechanisms (12Kawashima Y. 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Goldstein J.L. in the of with 1999; PubMed Scopus Google Scholar, of and on hepatic desaturase gene Res. 2001; PubMed Scopus Google Scholar). dietary and influences to play an important role in transcription regulation of delta-6 desaturase, genetic are important as well for the level and composition of HUFAs in human is the FADS gene cluster on with a of the and FADS2 which the delta-5 and delta-6 desaturase, A desaturase is in the from the FADS2 gene in a A. H. Weber B.H. and of of the human fatty acid desaturase PubMed Scopus Google Scholar). Several gene studies reported an of a of single nucleotide polymorphisms (SNPs) in the FADS gene cluster with fatty acid composition in human H. M. I. H. T. B. J. genetic of the FADS2 gene cluster and their are associated with the fatty acid composition in PubMed Scopus Google Scholar, N. E. M. N. P. et of the FADS gene cluster are associated with polyunsaturated fatty acids in a of with 2008; 43: PubMed Scopus Google Scholar, P. J. N. S. T. J. for an genetic of the fatty acid desaturase fatty acid desaturase gene cluster and the fatty acid composition of J. Nutr. 2009; PubMed Scopus Google Scholar, A. E. P. H. gene and the of J. Nutr. PubMed Scopus Google Scholar). These results were by which for the first SNP with and the by this C. E. M. T. J. et a study of in human 2008; PubMed Scopus Google Scholar). several studies reported an of FADS polymorphisms with polyunsaturated fatty acids T. J. A. A. S. A. et study of polyunsaturated fatty acids in the 2009; PubMed Scopus Google Scholar) and complex like and S. I. T. et levels and in 2009; PubMed Scopus Google Scholar, S. S. Y. T. et at to 2009; PubMed Scopus Google Scholar, C. A. S. J. T. M. et of in a from a 2009; PubMed Scopus Google Scholar). In the first study H. M. I. H. T. B. 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We the binding of ELK1 protein to the by of proteins from the region SNP rs968567 with either the allele or the minor containing an ELK1 binding P. J. of the ETS DNA-binding Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) was as positive The and containing proteins as well as the with the proteins were and a human ELK1 was to presence of ELK1 protein in the A to ELK1 was in the of the positive that ELK1 from is to to the and The of ELK1 in the of the minor which was in the of the binding of ELK1 to the FADS2 promoter the minor allele is studies showed an of delta-6 and delta-5 desaturase gene polymorphisms with HUFA level and composition in human by an accumulation of desaturase and a in desaturase products H. M. I. H. T. B. J. genetic of the FADS2 gene cluster and their are associated with the fatty acid composition in PubMed Scopus Google Scholar, N. E. M. N. P. et of the FADS gene cluster are associated with polyunsaturated fatty acids in a of with 2008; 43: PubMed Scopus Google Scholar, P. J. N. S. T. J. for an genetic of the fatty acid desaturase fatty acid desaturase gene cluster and the fatty acid composition of J. Nutr. 2009; PubMed Scopus Google Scholar, A. E. P. H. gene and the of J. Nutr. PubMed Scopus Google Scholar, C. E. M. T. J. et a study of in human 2008; PubMed Scopus Google Scholar). that the desaturase activity is regulated by nutritional and influences by genetic The observed of HUFA levels and composition in human due to the polymorphisms several important physiological processes and is to the development of complex The effect of FADS polymorphisms on brain development been shown by et al. A. B. J. A. H. of effects on the by genetic in fatty acid PubMed Scopus Google who reported a modulation of the positive effect of on development of by polymorphisms in the FADS gene cluster in two The importance of an delta-6 desaturase on eicosanoid synthesis and membrane composition was by of two fads2 knockout mice (4Stoffel W. Holz B. Jenke B. Binczek E. Gunter R.H. Kiss C. Karakesisoglou I. Thevis M. Weber A.A. Arnhold S. et al.Delta6-desaturase (FADS2) deficiency unveils the role of omega3- and omega6-polyunsaturated fatty acids.EMBO J. 2008; 27: 2281-2292Crossref PubMed Scopus (174) Google Scholar, C.K. Nara T.Y. Roqueta-Rivera M. Radlowski E.C. Lawrence P. Zhang Y. Cho B.H. Segre M. Hess R.A. Brenna J.T. et al.Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration.J Lipid Res. 2009; (Epub ahead of print. April 7, 2009.)Abstract Full Text Full Text PDF Scopus (126) Google Scholar). The that is a direct effect of FADS polymorphisms on the of fatty been by et al. H. M. I. H. T. B. J. genetic of the FADS2 gene cluster and their are associated with the fatty acid composition in PubMed Scopus Google who reported an of the FADS gene cluster with and after for study reported an of FADS with inflammation and N. P. T. E. M. S. et and desaturase activity by the of arachidonic acid to acid are associated with inflammation and J. Nutr. 2008; PubMed Scopus Google Scholar). at a role of delta-6 desaturase in regulating fatty acid composition in human to to the influence of genetic polymorphisms on the regulation of the human activity are to the role of desaturases in the development of fatty complex studies have reported associations of several in the FADS gene cluster with HUFA levels and composition in human and have to the of the influence of on the regulation of fatty acid synthesis H. M. I. H. T. B. J. genetic of the FADS2 gene cluster and their are associated with the fatty acid composition in PubMed Scopus Google Scholar, N. E. M. N. P. et of the FADS gene cluster are associated with polyunsaturated fatty acids in a of with 2008; 43: PubMed Scopus Google Scholar, P. J. N. S. T. J. for an genetic of the fatty acid desaturase fatty acid desaturase gene cluster and the fatty acid composition of J. Nutr. 2009; PubMed Scopus Google Scholar, A. E. P. H. gene and the of J. Nutr. PubMed Scopus Google Scholar, C. E. M. T. J. et a study of in human 2008; PubMed Scopus Google Scholar). However, the functional are to The of in the FADS gene cluster that polymorphisms in this region are in and of are highly The functional associations of other in and be by studies for this are to the effect of the associated on the molecular level and by this the luciferase reporter gene showed that of the two FADS2 promoter polymorphisms is in a region that to be important for transcription the minor of a significant effect on promoter the minor allele of rs968567 highly promoter activity with the containing both The effect was the in cell the response in cells was and significant for both transcription regulation is T. B. M. J. regulation of human and in PubMed Scopus Google this is due to the expression pattern of involved transcription binding of transcription to the is the for the observed effects in the luciferase molecular were by several binding in the and their for protein several protein complexes were shown to to the of by In the of a allele-specific binding of at least two protein complexes was shown by a The minor allele of rs968567 the binding in to the binding be shown for the region containing for a influence of the rs968567 polymorphism on transcription regulation of the FADS2 In this was shown that the FADS2 promoter region SNP rs968567 promoter which the allele of SNP rs968567 is by the minor We that this effect be caused by allele-specific binding of transcription in of additional binding and in the the allele of rs968567 was by the minor was by that allele-specific binding of at least two protein complexes to this promoter of levels of the transcription and expression levels of FADS2 in a highly significant ELK1 and with a effect in for the rs968567 minor We the of PPARA and SREBP1 with FADS2 as positive two transcription are to FADS2 transcription (1Nakamura M.T. Nara T.Y. Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases.Annu. Rev. Nutr. 2004; 24: 345-376Crossref PubMed Scopus (837) Google Scholar). The significant results of positive of the expression and the significant ELK1 and ELK1 is a member of the ETS domain of transcription factors, was first in M. A. genes on X and PubMed Scopus Google and is for role in the regulation of early S. of a protein by response factor to the response Full Text PDF PubMed Scopus Google Scholar) and T. complex and transcription of response in 1999; PubMed Scopus Google by complexes with response factor on the response of gene R.A. A. protein is to the regulatory factor PubMed Scopus Google Scholar). a role of ELK1 in been reported We binding of ELK1 protein to the binding in the FADS2 gene promoter by and ELK1 in the were the allele of SNP rs968567 was by the minor effect is in with the and ELK1 as a of FADS2 gene transcription in an allele-specific The that FADS2 and ELK1 expression significant results for both with effect for the that ELK1 to the FADS2 promoter in the presence of the with that were to ELK1 protein in that in be an additional functional ELK1 binding in another region of the FADS2 of which several are by et al. A.A. A nucleotide in the regulatory region of FADS2 to human fatty acid Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar) a study in that with functional of the The to the molecular mechanism of FADS2 deficiency in from a with like and shown to be caused by a deficiency of delta-6 desaturase S.D. M. A.A. of a fatty acid deficiency in human Lipid Res. 2001; Full Text Full Text PDF PubMed Google Scholar). the FADS2 promoter region of from and the to from a in the which to the allele of reporter gene assays in a mouse cell with promoter from allele and in promoter activity the allele was result be in of human cell be that et al. a mouse cell for their which a of transcription with human cell or that another polymorphism in the caused the effect in the study of et al. In this showed that polymorphism rs968567 influences FADS2 gene promoter activity and DNA-binding of One of the proteins binding to this region in an allele-specific manner was shown to be the transcription factor are to completely the of ELK1 with the FADS2 gene promoter or other functional in the gene and on FADS2 gene expression in
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