Abstract
Repetitive DNA sequences form a substantial portion of eukaryotic genomes and exist as members of families that differ in copy number, length, and sequence. Various functions, including chromosomal integrity, gene regulation, and gene rearrangement have been ascribed to repetitive DNA. Although there is evidence that some repetitive sequences may participate in gene regulation, little is known about how their own expression may be regulated. During the course of gene trapping experiments with embryonic stem (ES) cells, we identified a novel class of expressed repetitive sequences in the mouse, using 5′ rapid amplification of cDNA ends-polymerase chain reaction (5′ RACE-PCR) to clone fusion transcripts from these lines. The expression of these repeats was induced by retinoic acid (RA) in cultured ES cells examined by Northern blot analyses. In vivo, their expression was spatially restricted in embryos and in the adult brain as determined by RNA in situ hybridization. We designated this family of sequences as Dr (developmentally regulated) repeats. The members of the Dr family, identified by cDNA cloning and through database search, are highly similar in sequence and show peculiar structural features. Our results suggest the expression of Dr-containing transcripts may be part of an ES cell differentiation program triggered by RA. The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession numbers U51725 (Dr-1), U51726 (Dr-2), and U51727 (Dr-3).
Similar content being viewed by others
References
Agabian, N. (1990). Trans splicing of nuclear pre-mRNAs. Cell 61, 1157–1160.
Aizawa, H., Sekine, Y., Takemura, R., Zhang, Z., Nangaku, M., Hirokawa, N. (1992). Kinesin family in murine central nervous system. J. Cell Biol. 1993, 1287–1296.
Bennett, K.L., Hill, R.E., Pietras, D.F., Woodworth-Gutai, M., KaneHaas, C., Houston, J.M., Heath, J.K., Hastie, N.D. (1984). Most highly repeated dispersed DNA families in the mouse genome. Mol. Cell. Biol. 4, 1561–1571.
Blumenthal, T., Thomas, J. (1988). Cis and trans mRNA splicing in C. elegans. Trends Genet. 4, 305–308.
Brini, A.T., Lee, G.M., Kinet, J.-P. (1993). Involvement of Alu sequences in the cell-specific regulation of transcription of the γ chain of Fc and T cell receptors. J. Biol. Chem. 268, 1355–1361.
Britten, R.J., Davidson, E.H. (1969). Gene regulation for higher cells: a theory. Science 165, 349–357.
Chomczynski, P., Sacchi, N. (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159.
Darnell, J., Lodish, H., Baltimore, D. (1990). Molecular Cell Biology. (New York: Scientific American Books).
Decoville, M., Moreau, P., Viegas-Pequignot, E., Locker, D. (1992). Genomic organization and nucleotide sequence of a long mosaic repetitive DNA in the mouse genome. Mamm. Genome 2, 172–185.
Deininger, P.L., Batzer, M.A., Hutchison III, C.A., Edgell, M.H. (1992). Master genes in mammalian repetitive DNA amplification. Trends Genet. 8, 307–311.
Edwards, D.R., Parfett, L.J., Denhardt, D.T. (1985). Transcriptional regulation of two serum-induced RNAs in mouse fibroblasts: equivalence of one species to B2 repetitive elements. Mol. Cell. Biol. 5, 3280–3288.
Eul, J., Graessmann, M., Graessmann, A. (1995). Experimental evidence for RNA trans-splicing in mammalian cells. EMBO J. 14, 3226–3235.
Feng, G.-S., Shen, R., Heng, H.H.Q., Tsui, L.-C., Kazlauskas, A., Pawson, T. (1994). Receptor-binding, tyrosine phosphorylation and chromosome localization of the mouse SH2-containing phosphotyrosine phosphatase Syp. Oncogene 9, 1545–1550.
Forrester, L., Nagy, A., Sam, M., Watt, A., Stevenson, L., Bernstein, A., Joyner, A.L., Wurst, W. (1996). Induction gene trapping in ES cells: identification of developmentally regulated genes that respond to retinoic acid. Proc. Natl. Acad. Sci. USA 93, 1677–1682.
Hardman, N. (1986). Structure and function of repetitive DNA in eukaryotes. Biochem. J. 234, 1–11.
Hellmann-Blumberg, U., McCarthy Hintz, M.F., Gatewood, J.M., Schmid, C.W. (1993). Developmental differences in methylation of human Alu repeats. Mol. Cell. Biol. 13, 4523–4530.
Heng, H.H.Q., Squire, J., Tsui, L.-C. (1992). High resolution mapping of mammalian genes by in situ hybridization to free chromatin. Proc. Natl. Acad. Sci. USA 89, 9509–9513.
Heng, H.H.Q., Xiao, H., Shi, X.-M., Greenblatt, J., Tsui, L.-C. (1994). Genes encoding general initiation factors for RNA polymerase II transcription are dispersed in the human genome. Hum. Mol. Genet. 3, 61–64.
Henthorn, P.S., Mager, D.L., Huisman, T.H., Smithies, O. (1986). A gene deletion ending within a complex array of repeated sequences 3 ′ to the human beta-globin gene cluster. Proc. Natl. Acad. Sci. USA 83, 5194–5198.
Hobbs, H.H., Brown, M.S., Goldstein, J.L., Russell, D.W. (1986). Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia. J. Biol. Chem. 261, 13114–13120.
Hogan, B., Beddington, R., Costantini, F., Lacy, E. (1994). Manipulating the Mouse Embryo, A Laboratory Manual. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press).
Huang, L.S., Ripps, M.E., Korman, S.H., Deckelbaum, R.J., Breslow, J.L. (1989). Hypobetalipoproteinemia due to an apolipoprotein B gene exon 21 deletion derived by Alu-Alu recombination. J. Biol. Chem. 264, 11394–11400.
Kato, S., Anderson, R.A., Camerini-Otero, R.O. (1986). Foreign DNA introduced by calcium phosphate is integrated into repetitive DNA elements of the mouse L cell genome. Mol. Cell. Biol. 6, 1787–1795.
Koga, Y., Lindstrom, E., Fenyo, E.M., Wigzell, H., Mak, T.W. (1988). High levels of heterodisperse RNAs accumulate in T cells infected with human immunodeficiency virus and in normal thymocytes. Proc. Natl. Acad. Sci. USA 85, 4521–4525.
Krontiris, T.G. (1995). Minisatellites and human disease. Science 269, 1682–1683.
Lania, L., Pannuti, A., La Mantia, G., Basilico, C. (1987). The transcription of B2 repeated sequences is regulated during the transition from quiescent to proliferative state in cultured rodent cells. FEBS Lett. 219, 400–404.
Maichele, A.J., Farwell, N.J., Chamberlain, J.S. (1993). A B2 repeat insertion generates alternate structures of the mouse muscle γ-phosphorylase kinase gene. Genomics 16, 139–149.
Mark, W.H., Signorelli, K., Blum, M., Kwee, L., Lacy, E. (1992). Genomic structure of the locus associated with an insertional mutation in line 4 transgenic mice. Genomics 13, 159–166.
Matthews, K.R., Tschudi, C., Ullu, E. (1994). A common pyrimidinerich motif governs trans-splicing and polyadenylation of tubulin polycistronic pre-mRNA in trypanosomes. Genes & Dev. 8, 491–501.
Murnane, J.P., Morales, J.F. (1995). Use of a mammalian interspersed repetitive (MIR) element in the coding and processing sequences of mammalian genes. Nucleic Acids Res. 23, 2837–2839.
Murphy, D., Brickell, P.M., Latchman, D.S., Willison, K., Rigby, P.W.J. (1983). Transcripts regulated during normal embryonic development and oncogenic transformation share a repetitive element. Cell 35, 865–871.
Nicholls, R.D., Fischel-Ghodsian, N., Higgs, D.R. (1987). Recombination at the humans alpha-globin gene cluster: sequence features and topological constraints. Cell 49, 369–378.
Nilsen, T.W. (1989). Trans-splicing in nematodes. Exp. Parasitol. 69, 413–416.
Ogura, T., Evans, R.M. (1995). A retinoic acid-triggered cascade of HOXB1 gene activation. Proc. Natl. Acad. Sci. USA 92, 387–391.
Perlman, S., Phillips, C.A., Bishop, J.D. (1976). A study of foldback DNA. Cell 8, 33–42.
Rouyer, F., Simmler, M.C., Page, D.C., Weissenbach, J. (1987). A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination. Cell 51, 417–425.
Rudert, F., Bronner, S., Garnier, J.M., Dolle, P. (1995). Transcripts from opposite strands of gamma satellite DNA are differentially expressed during mouse development. Mamm. Genome 6, 76–83.
Rudiger, N.S., Hansen, P.S., Jorgensen, M., Faergeman, O., Bolund, L., Gregersen, N. (1991). Repetitive sequences involved in the recombination leading to deletion of exon 5 of the low-density-lipoprotein receptor gene in a patient with familial hypercholesterolemia. Eur. J. Biochem. 198, 107–111.
Rudiger, N.S., Gregersen, N., Kielland-Brandt, C. (1995). One short well conserved region of Alu-sequences is involved in human gene rearrangements and has homology with prokaryotic chi. Nucleic Acids Res. 23, 256–260.
Saffer, J.D., Thurston, S J. (1989). A negative regulatory element with properties similar to those of enhancers is contained within an Alu sequence. Mol. Cell. Biol. 9, 355–364.
Saksela, K., Baltimore, D. (1993). Negative regulation of immunoglobulin kappa light-chain gene transcription by a short sequence homologous to the murine B1 repetitive element. Mol. Cell. Biol. 13, 3698–3705.
Sambrook, J., Fritsch, E.F., Maniatis, T. (1989). Molecular Cloning, A Laboratory Manual. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press).
Schmid, C., Maraia, R. (1992). Transcriptional regulation and transpositional selection of active SINE sequences. Curr. Opin. Genet. Dev. 2, 874–882.
Schmid, C.W., Deininger, P.L. (1975). Sequence organization of the human genome. Cell 6, 345–358.
Silver, L.M. (1995). Mouse Genetics, Concepts and Applications. (New York: Oxford University Press).
Simeone, A., Acampora, D., Arcioni, L., Andrews, P.W., Boncinelli, E., Mavilio, F. (1990). Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells. Nature 346, 763–766.
Singh, K., Carey, M., Saragosti, S., Botchan, M. (1985). Expression of enhanced levels of small RNA polymerase III transcripts encoded by the B2 repeats in simian virus 40-transformed mouse cells. Nature 314, 553–556.
Smidt, M., Kirsch, I., Ratner, L. (1990). Deletion of Alu sequences in the fifth c-sis intron in individuals with meningiomas. J. Clin. Invest. 86, 1151–1157.
Tini, M., Otulakowski, G., Breitman, M.L., Tsui, L.C., Giguere, V. (1993). An everted repeat mediates retinoic acid induction of the γ-crystallin gene: evidence of a direct role for retinoids in lens development. Genes & Dev. 7, 295–307.
Tomilin, N.V., Iguchi-Ariga, S.M.M., Ariga, H. (1990). Transcription and replication silencer element is present within conserved region of human Alu repeats interacting with nuclear protein. FEBS Lett. 263, 69–72.
Vanin, E.F., Henthorn, P.S., Kioussis, D., Grosveld, F., Smithies, O. (1983). Unexpected relationships between four large deletions in the human beta-globin gene cluster. Cell 35, 701–709.
Vansant, G., Reynolds, W.F. (1995). The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element. Proc. Natl. Acad. Sci. USA 92, 8229–9233.
Vellard, M., Sureau, A., Soret, J., Martinerie, C., Perbol, B. (1992). A potential splicing factor is encoded by the opposite strand of the (ranispliced c-myb exon. Proc. Natl. Acad. Sci. USA 89, 2511–2515.
Vidal, F., Mougneau, E., Glaichenhaus, N., Vaigot, P., Darmon, M., Cuzin, F. (1993). Coordinated posttranscriptional control of gene expression by modular elements including Alu-like repetitive sequences. Proc. Natl. Acad. Sci. USA 90, 208–212.
Wallace, M.R., Andersen, L.B., Saulino, A.M., Gregory, P.E., Glover, T.W., Collins, F.S. (1991). A de novo Alu insertion results in neurofibromatosis type 1. Nature 353, 864–866.
Watson, J.B., Sutcliffe, J.G. (1987). Primate brain-specific cytoplasmic transcript of the Alu repeat family. Mol. Cell. Biol. 7, 3324–3327.
Wilkie, T.M., Palmiter, R.D. (1987). Analysis of the integrant in the MyK-103 transgenic mice in which males fail to transmit the integrant. Mol. Cell. Biol. 7, 1646–1655.
Wilkie, T.M., Braun, R.E., Ehrman, W.J., Palmiter, R.D., Hammer, R.E. (1991). Germ-line intrachromosomal recombination restores fertility in transgenic MyK-103 male mice. Genes & Dev. 5, 38–48.
Young, M.W. (1979). Middle repetitive DNA: a fluid component of the Drosophila genome. Proc. Natl. Acad. Sci. USA 76, 6274–6278.
Youssoufian, H., Lodish, H.F. (1993). Transcriptional inhibition of the murine erythropoietin receptor gene by an upstream repetitive element. Mol. Cell. Biol. 13, 98–104.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sam, M., Wurst, W., Forrester, L. et al. A novel family of repeat sequences in the mouse genome responsive to retinoic acid. Mammalian Genome 7, 741–748 (1996). https://doi.org/10.1007/s003359900224
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s003359900224