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Genomic organization of IFI16, an interferon-inducible gene whose expression is associated with human myeloid cell differentiation: correlation of predicted protein domains with exon organization

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Abstract

The human IFI16 gene is a member of an interferon-inducible family of mouse and human genes closely linked on syntenic regions of chromosome 1. Expression of these genes is largely restricted to hemopoietic cells, and is associated with the differentiation of cells of the myeloid lineages. As a prelude to defining the mechanisms governing IFI16 expression, we have deduced its genomic organization using a combination of genomic cloning and polymerase chain reaction amplification of genomic DNA. IFI16 consists of ten exons and nine intervening introns spanning at least 28 kilobases (kb) of DNA. The reiterated domain structure of IFI16 protein is closely reflected in its intron/exon boundaries, and may represent the evolutionary fusion of several independent functional domains. Thus, exon 1 consists of 5' untranslated (UT) sequences and contains sequence motifs that may confer interferon-inducibility, and exon 2 encodes the lysine-rich amino-terminal (“K”) region, which possesses DNA-binding activity. Exon 3 codes for a domain which is poorly conserved between family members, except for a strongly retained basic motif likely to provide nuclear localization. The first of two 200 amino acid repeat domains that are the hallmark of this family (domain A) is represented jointly on exons 4 and 5, which are reiterated as exons 8 and 9, respectively, to encode the second 200 amino acid domain (B). Two intervening serine-threonine-rich domains (C and C'), unique to IFI16, are each encoded by single exons of identical length (exons 5 and 6). These domains are predicted to encode semi-rigid “spacer” domains between the 200 amino acid repeats. The reiterated nature of exons 4 to 6 and the insertion of introns into a single reading frame strongly suggest that IFI16 and related genes arose by a series of exon duplications, some of which antedated speciation into mouse and humans. Several alternative mRNA cap sites downstream of a TATA consensus sequence were defined, using primer extension analysis of mRNA. Sequencing of ~1.7 kb of DNA upstream of this region revealed no recognizable consensus elements for induction by interferon-α (interferon-α/ß-stimulated response elements), but two motifs resembling interferon-γ activation sites were located. IFNs α and γ both induce IFI16 mRNA expression in myeloid cells. Interferon-α inducibility of IFI16 may be regulated by an interferon-α/ß-stimulated response consensus element in the 5' UT exon, as a similar motif is conserved in the corresponding position in the related myeloid cell nuclear differentiation antigen gene. An interferon-γ-activation site consensus was also located in this region of IFI16.

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References

  • Adams, M. D., Kerlavage, A. R., Fields, C., and Venter, J. C. 3,400 new expressed sequence tags identify diversity of transcripts in human brain. Nature Genetics 4: 256–267, 1993

    Google Scholar 

  • Briggs, J. A., Burrus, G. R., Stickney, B. D., and Briggs, R. C. Cloning and expression of the human myeloid cell nuclear differentiation antigen: regulation by interferon α. J Cell Biochem 49: 82–92, 1992

    Google Scholar 

  • Briggs, R. C., Dworkin, L., Briggs, J., Dessypris, E., Stein, J., Stein, G., and Lian, G. Interferon α selectively affects expression of the human myeloid cell nuclear differentiation antigen in late stage cells in the monocytic but not the granulocytic lineage. J Cell Biochem 54: 198–206, 1994a

    Google Scholar 

  • Briggs, R. C., Briggs, J. A., Ozer, J., Sealy, L., Dworkin, L. L., Kingsmore, S. F., Seldin, M. F., Kaur, G. P., Athwal, R. S., and Dessypris, E. N. The human myeloid cell nuclear differentiation antigen gene is one of at least two related interferon-inducible genes located at chromosome 1q that are expressed specifically in hematopoietic cells. Blood 83: 1994b

  • Burrus, G. R., Briggs, J. A., and Briggs, R. C. Characterization of the human myeloid cell nuclear differentiation antigen: relationship to interferon-inducible proteins. J Cell Biochem 48: 190–202, 1992

    Google Scholar 

  • Chen E. Y., and Seeberg, P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA 4: 165–170, 1985

    Google Scholar 

  • Chivria, J. C., Wedrychowicz, Young, H. A., and Hardy, K. J. A model of human cytokine regulation based on transfection of γ interferon gene fragments into isolated peripheral T lymphocytes. J Exp Med 172: 661–664, 1990

    Google Scholar 

  • Chou, R. H., Chervenick, P. A., and Barch, D. R. Appearance of a new nucleosomal protein during differentation of human leukemia (HL-60) cells. Science 223: 1420–1423, 1984

    Google Scholar 

  • Choubey, D. and Lengyel, P. Interferon action: nucleolar and nucleoplasmic localization of the interferon-inducible 72-kD protein that is encoded by the Ifi204 gene from the Gene 200 cluster. J Cell Biol 116: 1333–1341, 1992

    Google Scholar 

  • Choubey, D. and Lengyel, P. Interferon action: cytoplasmic and nuclear localization of the interferon-inducible 52-kDa protein that is encoded by the Ifi202 gene from the Gene 200 cluster. J Interferon Res 13: 43–52, 1993

    Google Scholar 

  • Choubey, D., Snoddy, J., Chaturvedi, V., Toniato, E., Opdenakker, G., Thakur, A., Samanta, H., Engel, D. A., and Lengyel, P. Interferons as gene activators: indications for repeated gene duplication during the evolution of a cluster of interferon-activatable genes on murine chromosome 1. J Biol Chem 264: 17182–17189, 1989

    Google Scholar 

  • Dawson, M. and Trapani, J. A. The IFI16 gene encodes a nuclear protein whose expression is induced by interferons in human myeloid leukemia cell lines. J Cell Biochem (in press)

  • Decker, T., Lew, D. J., Mirkovitch, J., and Darnell, J. E. Cytoplasmic activation of GAF, an IFN-γ-regulated DNA binding factor. EMBO J 10: 927–932, 1991

    Google Scholar 

  • Dietsch, E., Osman, N., McKenzie, I. F. C., Garson, O. M., and Hogarth, P. M. The human FCG1 gene encoding FcγR1 maps to chromosome 1q21. Immunogenetics 38: 307–309, 1993

    Google Scholar 

  • Duhl, D. M., Gaczynski, M., Olinski, R., and Briggs, R. C. Intranuclear distribution of the human myeloid cell differentiation antigen in HL-60 cells. J Cell Physiol 141: 148–153, 1989

    Google Scholar 

  • Engel, D. A., Samanta, H., Brawner, M. E., and Lengyel, P. Interferon action: transcriptional control of a gene specifying a 56,000-Da protein in Ehrlich Ascites Tumor Cells. Virology 142: 389–397, 1985

    Google Scholar 

  • Engel, D., Snoddy, J., Toniato, E., and Lengyel, P. Interferons as gene activators: close linkage of two interferon-activatable murine genes. Virology 166: 24–29, 1988

    Google Scholar 

  • Gaczynski, M., Briggs, J. A., Wedrychowski, A., Olinski, R., Uskokovic, M., Lian, J. B., Stein, G. S., and Briggs, R. C. cisdiamminedichloroplatinum (II) cross-linking of the human myeloid cell nuclear differentiation to DNA in HL-60 cells following 1,25-dihydroxy vitamin D3-induced monocyte differentiation. Cancer Research 50: 1183–1188, 1990

    Google Scholar 

  • Goldberger, A., Hnilica, L. S., Casey, S. B., and Briggs, R. C. Properties of a nuclear protein marker of human myeloid cell differentiation. J Biol Chem 261: 4726–4731, 1986

    Google Scholar 

  • Goldberger, A., Brewer, G., Hnilica, L. S., and Briggs, R. C. Non-histone protein antigen profiles of five leukemic cell lines reflect the extent of myeloid cell differentiation. Blood 63: 701–710, 1984

    Google Scholar 

  • Hromas, R., Collins, S. J., Hickstein, D., Raskind, W., Deaven, L. L., O'Hara, P., Hagen, F. S., Kaushansky, K. A retinoic acid-responsive human zinc finger gene, MZF-1, preferentially expressed in myeloid cells. J Chem Biol 266: 14183–14187, 1991

    Google Scholar 

  • Jans, D. A., Ackermann, M. J., Bischoff, J. R., Beach, D. H., and Peters, R. p34 cdc2-mediated phosphorylation at T124 inhibits nuclear import of SV-40 antigen proteins. J Cell Biol 115: 1203–1212, 1991

    Google Scholar 

  • John, J., McKendry, R., Pellegrini, S., Flavell, D., Kerr, I. M., and Stark, G. R. Isolation and characterization of a new mutant cell line unresponsive to alpha and beta interferons. Mol Cell Biol 11: 4189–4195, 1991

    Google Scholar 

  • Kalderon, D., Roberts, B. L., Richardson, W. D., and Smith, A. E. A short amino acid sequence able to specify nuclear localization. Cell 39: 499–509, 1984

    Google Scholar 

  • Kanno, Y., Kozak, C. A., Schindler, C., Driggers, P. H., Ennist, E., Gleason, S. L., Darnell, J. E., and Ozato, K. The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon responsive element, to which an ISGF3α subunit (or similar) molecule binds. Mol Cell Biol 13: 3951–3963, 1993

    Google Scholar 

  • Kingsmore, S. F., Snoddy, J., Choubey, D., Lengyel, P., and Seldin, M. F. Physical mapping of interferon-activated genes, serum amyloid P-component, and α-spectrin on mouse chromosome 1. Immunogenetics 30: 169–174, 1989a

    Google Scholar 

  • Kingsmore, S. F., Watson, M. L., Howard, T. A., and Seldin, M. F. A 6000 kb segment of chromosome 1 is conserved in human and mouse. EMBO J 8: 4073–4080, 1989b

    Google Scholar 

  • Lautner-Rieske, A., Huber, C., Meindl, A., Pargent, W., Schable, K. F., Thiebe, R., Zocher, I., and Zachau, H. G. The human immunoglobulin K locus. Characterization of the duplicated A regions. Eur J Immunol 22: 1023–1029, 1992

    Google Scholar 

  • Levy, D. E., Kessler, D. S., Pine, R., Reich, N., and Darnell, J. E. Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev 2: 383–393, 1988

    Google Scholar 

  • Levy, D. E., Kessler, D. S., Pine, R., and Darnell, J. E. Cytoplasmic activation of ISGF3, the putative regulator of interferon-α-stimulated transcription reconstituted in vitro. Genes Dev 3: 1362–1371, 1989

    Google Scholar 

  • Lew, D. J., Decker, T., Strehlow, I., and Darnell, J. E. Overlapping elements of the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons. Mol Cell Biol 11: 182–191, 1991

    Google Scholar 

  • Mount, S. M. A catalogue of splice junction sequences. Nucleic Acids Res 10: 459–472, 1982

    CAS  PubMed  Google Scholar 

  • Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., and Cone, R. D. The cloning of a family of genes that encode melanocortin receptors. Science 257: 1248–251, 1992

    Google Scholar 

  • Murao, S., Epstein, A. L., Levenger, C. V., and Huberman, E. Expression of maturation-specific nuclear antigens in differentiating human myeloid leukemis cells. Cancer Research 45: 791–795, 1985

    Google Scholar 

  • Ogawa, M. Differentiation and proliferation of haematopoietic stem cells. Blood 13: 495–500, 1992

    Google Scholar 

  • Opdenakker, G., Snoddy, J., Choubey, D., Toniato, E., Pravtcheva, D. D., Seldin, M. F., Ruddle, M. F., and Lengyel, P. Interferons as gene activators: a cluster of six interferon-activatable genes is linked to the erythroid α-spectrin locus on murine chromosome 1. Virology 171: 568–578, 1989

    Google Scholar 

  • Pearse, R. N., Feinman, R., and Ravetch, J. V. Characterization of the promoter of the gene encoding the high affinity IgG receptor: transcriptional induction by γ-interferon is mediated through common DNA response elements. Proc Natl Acad Sci USA 88: 11305–11309, 1991

    Google Scholar 

  • Pellegrini, S., and Schindler, C. Early events in signalling by interferons. Trends Biol Sci 18: 338–342, 1993

    Google Scholar 

  • Pestka, S., Langer, J. A., Zoon, K. C., and Samuel, C. E. Interferons and their actions. Annu Rev Biochem 56: 727–777, 1987

    Google Scholar 

  • Porter, A. C., Chernajofsky, Y., Dale, T. C., Gilbert, C. S., Stark, G. R., and Kerr, I. M. Interferons response elements of the human gene, 6–16. EMBO J 7: 85–92, 1988

    Google Scholar 

  • Rabiloud, T., Pennetier, J. L., Hibner, U., Vincens, P., Tarroux, P., and Rougeon, F. Stage transitions in B-lymphocyte differentiation correlate with limited variations in nuclear proteins. Proc Natl Acad Sci USA 88: 1830–1834, 1991

    Google Scholar 

  • Reid, L. E., Brasnett, A. H., Gilbert, C. S., Porter, A. C., Gewert, D. R., Stark, G. R., and Kerr, I. M. A single DNA response element can confer inducibility with both α- and γ-interferons. Proc Natl Acad Sci USA 86: 940–844, 1989

    Google Scholar 

  • Rihs, H.-P., Jans, D. A., Fan, H., and Peters, R. The rate of nuclear cytoplastic protein transport the casein kinase II site flanking the nuclear localization signal of the SV40 T-antigen. EMBO J 10: 633–639, 1991

    Google Scholar 

  • Samanta, H., Engel, D. A., Chao, H. M., Thakur, A., Garcia--Blanco, M. A., and Lengyel, P. Interferons as gene activators. Cloning of the 5′ terminus and the control segment of an interferon activated gene. J Biol Chem 261: 11849–11858, 1986

    Google Scholar 

  • Sambrook, J., Fritsch, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, 1989

    Google Scholar 

  • Sanger, F., Nicklen, S., and Coulson, A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74: 5463–5467, 1977

    CAS  PubMed  Google Scholar 

  • Schindler, C., Shuai, K., Prezioso, V. R., and Darnell, J. E. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257: 809–813, 1992

    Google Scholar 

  • Shuai, K., Schindler, C., Prezioso, V. R., and Darnell, J. E. Activation of transcription by IFN-Gg: tyrosine phosphorylation of a 91 kD DNA binding protein. Science 258: 1808–1812, 1992

    Google Scholar 

  • Tannenbaum, C. S., Major, J., Ohmori, Y., and Hamilton, T. A. A lipopolysaccharide-inducible macrophage gene (D3) is a new member of an interferon-inducible gene cluster and is selectively expressed in mononuclear phagocytes. J Leukoc Biol 53: 563–568, 1993

    Google Scholar 

  • Trapani, J. A., Browne, K. A., Dawson, M. J., Ramsay, R. G., Eddy, R. L., Shows, T. B., White, P. C., and Dupont, B. A novel gene constitutively expressed in human lymphoid cells is inducible with interferon-γ in myeloid cells. Immunogenetics 36: 369–376, 1992

    Google Scholar 

  • Velasquez, L., Fellous, M., Stark, G. R., and Pellegrini, S. A protein tyrosine kinase in the interferon α/β signaling pathway. Cell 70: 313–322, 1992

    Google Scholar 

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Authors and Affiliations

  1. Cellular Cytotoxicity Laboratory, Austin Research Institute, Austin Hospital, Studley Road, 3084, Heidelberg, VIC, Australia

    Joseph A. Trapani, Michelle Dawson, Vicki A. Apostolidis & Kylie A. Browne

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  1. Joseph A. Trapani
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  2. Michelle Dawson
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  3. Vicki A. Apostolidis
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The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession number M63838

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Trapani, J.A., Dawson, M., Apostolidis, V.A. et al. Genomic organization of IFI16, an interferon-inducible gene whose expression is associated with human myeloid cell differentiation: correlation of predicted protein domains with exon organization. Immunogenetics 40, 415–424 (1994). https://doi.org/10.1007/BF00177824

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