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J Cell Biol. 1995 Dec 2; 131(6): 1635–1647.
PMCID: PMC2120660

Nonrandom gene organization: structural arrangements of specific pre- mRNA transcription and splicing with SC-35 domains


This work demonstrates a highly nonrandom distribution of specific genes relative to nuclear domains enriched in splicing factors and poly(A)+ RNA, and provides evidence for the direct involvement of these in pre-mRNA metabolism. As investigated in hundreds of diploid fibroblasts, human collagen I alpha 1 and beta-actin DNA/RNA showed a very high degree of spatial association with SC-35 domains, whereas three nontranscribed genes, myosin heavy chain, neurotensin, and albumin, showed no such preferential association. Collagen I alpha 1 RNA accumulates within the more central region of the domain, whereas beta-actin RNA localizes at the periphery. A novel approach revealed that collagen RNA tracks are polarized, with the entire gene at one end, on the edge of the domain, and the RNA extending into the domain. Intron 26 is spliced within the RNA track at the domain periphery. Transcriptional inhibition studies show both the structure of the domain and the gene's relationship to it are not dependent upon the continued presence of accumulated collagen RNA, and that domains remaining after inhibition are not just storage sites. Results support a model reconciling light and electron microscopic observations which proposes that transcription of some specific genes occurs at the border of domains, which may also function in the assembly or distribution of RNA metabolic components. In contrast to the apparently random dispersal of total undefined hnRNA synthesis through interdomain space, transcription and splicing for some genes occurs preferentially at specific sites, and a high degree of individual pre-mRNA metabolism is compartmentalized with discrete SC-35 domains.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • al-Shawi R, Kinnaird J, Burke J, Bishop JO. Expression of a foreign gene in a line of transgenic mice is modulated by a chromosomal position effect. Mol Cell Biol. 1990 Mar;10(3):1192–1198. [PMC free article] [PubMed]
  • Barsh GS, Roush CL, Gelinas RE. DNA and chromatin structure of the human alpha 1 (I) collagen gene. J Biol Chem. 1984 Dec 10;259(23):14906–14913. [PubMed]
  • Bernhard W. A new staining procedure for electron microscopical cytology. J Ultrastruct Res. 1969 May;27(3):250–265. [PubMed]
  • Beyer AL, Osheim YN. Splice site selection, rate of splicing, and alternative splicing on nascent transcripts. Genes Dev. 1988 Jun;2(6):754–765. [PubMed]
  • Blencowe BJ, Nickerson JA, Issner R, Penman S, Sharp PA. Association of nuclear matrix antigens with exon-containing splicing complexes. J Cell Biol. 1994 Nov;127(3):593–607. [PMC free article] [PubMed]
  • Blobel G. Gene gating: a hypothesis. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8527–8529. [PMC free article] [PubMed]
  • Brasch K. Drug and metabolite-induced perturbations in nuclear structure and function: a review. Biochem Cell Biol. 1990 Feb;68(2):408–426. [PubMed]
  • Brawerman G. Determinants of messenger RNA stability. Cell. 1987 Jan 16;48(1):5–6. [PubMed]
  • Brawerman G. The Role of the poly(A) sequence in mammalian messenger RNA. CRC Crit Rev Biochem. 1981;10(1):1–38. [PubMed]
  • Bregman DB, Du L, van der Zee S, Warren SL. Transcription-dependent redistribution of the large subunit of RNA polymerase II to discrete nuclear domains. J Cell Biol. 1995 Apr;129(2):287–298. [PMC free article] [PubMed]
  • Brown CJ, Hendrich BD, Rupert JL, Lafrenière RG, Xing Y, Lawrence J, Willard HF. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992 Oct 30;71(3):527–542. [PubMed]
  • Carter KC. Spatial localization of pre-mRNA transcription and processing within the nucleus. Curr Opin Biotechnol. 1994 Dec;5(6):579–584. [PubMed]
  • Carter KC, Taneja KL, Lawrence JB. Discrete nuclear domains of poly(A) RNA and their relationship to the functional organization of the nucleus. J Cell Biol. 1991 Dec;115(5):1191–1202. [PMC free article] [PubMed]
  • Carter KC, Bowman D, Carrington W, Fogarty K, McNeil JA, Fay FS, Lawrence JB. A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus. Science. 1993 Feb 26;259(5099):1330–1335. [PubMed]
  • Comings DE. Arrangement of chromatin in the nucleus. Hum Genet. 1980 Feb;53(2):131–143. [PubMed]
  • Cremer T, Cremer C, Schneider T, Baumann H, Hens L, Kirsch-Volders M. Analysis of chromosome positions in the interphase nucleus of Chinese hamster cells by laser-UV-microirradiation experiments. Hum Genet. 1982;62(3):201–209. [PubMed]
  • Cremer T, Kurz A, Zirbel R, Dietzel S, Rinke B, Schröck E, Speicher MR, Mathieu U, Jauch A, Emmerich P, et al. Role of chromosome territories in the functional compartmentalization of the cell nucleus. Cold Spring Harb Symp Quant Biol. 1993;58:777–792. [PubMed]
  • Davis L, Cadrin M, Brown DL, Chaly N. Reversible disassembly of transcription domains in lymphocyte nuclei during inhibition of RNA synthesis by DRB. Biol Cell. 1993;78(3):163–180. [PubMed]
  • Fakan S. Perichromatin fibrils are in situ forms of nascent transcripts. Trends Cell Biol. 1994 Mar;4(3):86–90. [PubMed]
  • Fakan S, Bernhard W. Localisation of rapidly and slowly labelled nuclear RNA as visualized by high resolution autoradiography. Exp Cell Res. 1971 Jul;67(1):129–141. [PubMed]
  • Fakan S, Puvion E. The ultrastructural visualization of nucleolar and extranucleolar RNA synthesis and distribution. Int Rev Cytol. 1980;65:255–299. [PubMed]
  • Fey EG, Krochmalnic G, Penman S. The nonchromatin substructures of the nucleus: the ribonucleoprotein (RNP)-containing and RNP-depleted matrices analyzed by sequential fractionation and resinless section electron microscopy. J Cell Biol. 1986 May;102(5):1654–1665. [PMC free article] [PubMed]
  • Fu XD. Specific commitment of different pre-mRNAs to splicing by single SR proteins. Nature. 1993 Sep 2;365(6441):82–85. [PubMed]
  • Fu XD, Maniatis T. Factor required for mammalian spliceosome assembly is localized to discrete regions in the nucleus. Nature. 1990 Feb 1;343(6257):437–441. [PubMed]
  • Genovese C, Brufsky A, Shapiro J, Rowe D. Detection of mutations in human type I collagen mRNA in osteogenesis imperfecta by indirect RNase protection. J Biol Chem. 1989 Jun 5;264(16):9632–9637. [PubMed]
  • Gerdes MG, Carter KC, Moen PT, Jr, Lawrence JB. Dynamic changes in the higher-level chromatin organization of specific sequences revealed by in situ hybridization to nuclear halos. J Cell Biol. 1994 Jul;126(2):289–304. [PMC free article] [PubMed]
  • Hawkins JW, Dugaiczyk A. The human serum albumin gene: structure of a unique locus. Gene. 1982 Jul-Aug;19(1):55–58. [PubMed]
  • Hendzel MJ, Bazett-Jones DP. RNA polymerase II transcription and the functional organization of the mammalian cell nucleus. Chromosoma. 1995 Feb;103(8):509–516. [PubMed]
  • Herman RC, Penman S. Multiple decay rates of heterogeneous nuclear RNA in HeLa cells. Biochemistry. 1977 Jul 26;16(15):3460–3465. [PubMed]
  • Herman RC, Williams JG, Penman S. Message and non-message sequences adjacent to poly(A) in steady state heterogeneous nuclear RNA of HeLa cells. Cell. 1976 Mar;7(3):429–437. [PubMed]
  • Hogan NC, Traverse KL, Sullivan DE, Pardue ML. The nucleus-limited Hsr-omega-n transcript is a polyadenylated RNA with a regulated intranuclear turnover. J Cell Biol. 1994 Apr;125(1):21–30. [PMC free article] [PubMed]
  • Huang S, Spector DL. Nascent pre-mRNA transcripts are associated with nuclear regions enriched in splicing factors. Genes Dev. 1991 Dec;5(12A):2288–2302. [PubMed]
  • Huang S, Deerinck TJ, Ellisman MH, Spector DL. In vivo analysis of the stability and transport of nuclear poly(A)+ RNA. J Cell Biol. 1994 Aug;126(4):877–899. [PMC free article] [PubMed]
  • Jackson DA. Structure-function relationships in eukaryotic nuclei. Bioessays. 1991 Jan;13(1):1–10. [PubMed]
  • Jackson DA, Hassan AB, Errington RJ, Cook PR. Visualization of focal sites of transcription within human nuclei. EMBO J. 1993 Mar;12(3):1059–1065. [PMC free article] [PubMed]
  • Jiménez-García LF, Spector DL. In vivo evidence that transcription and splicing are coordinated by a recruiting mechanism. Cell. 1993 Apr 9;73(1):47–59. [PubMed]
  • Johnson CV, Singer RH, Lawrence JB. Fluorescent detection of nuclear RNA and DNA: implications for genome organization. Methods Cell Biol. 1991;35:73–99. [PubMed]
  • Johnson CV, Cool DE, Glaccum MB, Green N, Fischer EH, Bruskin A, Hill DE, Lawrence JB. Isolation and mapping of human T-cell protein tyrosine phosphatase sequences: localization of genes and pseudogenes discriminated using fluorescence hybridization with genomic versus cDNA probes. Genomics. 1993 Jun;16(3):619–629. [PubMed]
  • Kislauskis E, Bullock B, McNeil S, Dobner PR. The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences. J Biol Chem. 1988 Apr 5;263(10):4963–4968. [PubMed]
  • Krause S, Fakan S, Weis K, Wahle E. Immunodetection of poly(A) binding protein II in the cell nucleus. Exp Cell Res. 1994 Sep;214(1):75–82. [PubMed]
  • Langer-Safer PR, Levine M, Ward DC. Immunological method for mapping genes on Drosophila polytene chromosomes. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4381–4385. [PMC free article] [PubMed]
  • Lawrence JB, Villnave CA, Singer RH. Sensitive, high-resolution chromatin and chromosome mapping in situ: presence and orientation of two closely integrated copies of EBV in a lymphoma line. Cell. 1988 Jan 15;52(1):51–61. [PubMed]
  • Lawrence JB, Singer RH, Marselle LM. Highly localized tracks of specific transcripts within interphase nuclei visualized by in situ hybridization. Cell. 1989 May 5;57(3):493–502. [PubMed]
  • Lawrence JB, Singer RH, McNeil JA. Interphase and metaphase resolution of different distances within the human dystrophin gene. Science. 1990 Aug 24;249(4971):928–932. [PubMed]
  • Lawrence JB, Carter KC, Xing X. Probing functional organization within the nucleus: is genome structure integrated with RNA metabolism? Cold Spring Harb Symp Quant Biol. 1993;58:807–818. [PubMed]
  • Leavitt J, Gunning P, Porreca P, Ng SY, Lin CS, Kedes L. Molecular cloning and characterization of mutant and wild-type human beta-actin genes. Mol Cell Biol. 1984 Oct;4(10):1961–1969. [PMC free article] [PubMed]
  • Lerner EA, Lerner MR, Janeway CA, Jr, Steitz JA. Monoclonal antibodies to nucleic acid-containing cellular constituents: probes for molecular biology and autoimmune disease. Proc Natl Acad Sci U S A. 1981 May;78(5):2737–2741. [PMC free article] [PubMed]
  • Lewin B. Units of transcription and translation: the relationship between heterogeneous nuclear RNA and messenger RNA. Cell. 1975 Jan;4(1):11–20. [PubMed]
  • Lichter P, Cremer T, Borden J, Manuelidis L, Ward DC. Delineation of individual human chromosomes in metaphase and interphase cells by in situ suppression hybridization using recombinant DNA libraries. Hum Genet. 1988 Nov;80(3):224–234. [PubMed]
  • Lompré AM, Nadal-Ginard B, Mahdavi V. Expression of the cardiac ventricular alpha- and beta-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem. 1984 May 25;259(10):6437–6446. [PubMed]
  • Manuelidis L. Different central nervous system cell types display distinct and nonrandom arrangements of satellite DNA sequences. Proc Natl Acad Sci U S A. 1984 May;81(10):3123–3127. [PMC free article] [PubMed]
  • Mattaj IW. RNA processing. Splicing in space. Nature. 1994 Dec 22;372(6508):727–728. [PubMed]
  • Moen PT, Jr, Smith KP, Lawrence JB. Compartmentalization of specific pre-mRNA metabolism: an emerging view. Hum Mol Genet. 1995;4(Spec No):1779–1789. [PubMed]
  • Nyman U, Hallman H, Hadlaczky G, Pettersson I, Sharp G, Ringertz NR. Intranuclear localization of snRNP antigens. J Cell Biol. 1986 Jan;102(1):137–144. [PMC free article] [PubMed]
  • O'Keefe RT, Mayeda A, Sadowski CL, Krainer AR, Spector DL. Disruption of pre-mRNA splicing in vivo results in reorganization of splicing factors. J Cell Biol. 1994 Feb;124(3):249–260. [PMC free article] [PubMed]
  • Pinkel D, Landegent J, Collins C, Fuscoe J, Segraves R, Lucas J, Gray J. Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9138–9142. [PMC free article] [PubMed]
  • Raska I, Andrade LE, Ochs RL, Chan EK, Chang CM, Roos G, Tan EM. Immunological and ultrastructural studies of the nuclear coiled body with autoimmune antibodies. Exp Cell Res. 1991 Jul;195(1):27–37. [PubMed]
  • Saez LJ, Gianola KM, McNally EM, Feghali R, Eddy R, Shows TB, Leinwand LA. Human cardiac myosin heavy chain genes and their linkage in the genome. Nucleic Acids Res. 1987 Jul 10;15(13):5443–5459. [PMC free article] [PubMed]
  • Salditt-Georgieff M, Harpold MM, Wilson MC, Darnell JE., Jr Large heterogeneous nuclear ribonucleic acid has three times as many 5' caps as polyadenylic acid segments, and most caps do not enter polyribosomes. Mol Cell Biol. 1981 Feb;1(2):179–187. [PMC free article] [PubMed]
  • Spector DL. Higher order nuclear organization: three-dimensional distribution of small nuclear ribonucleoprotein particles. Proc Natl Acad Sci U S A. 1990 Jan;87(1):147–151. [PMC free article] [PubMed]
  • Spector DL. Macromolecular domains within the cell nucleus. Annu Rev Cell Biol. 1993;9:265–315. [PubMed]
  • Spector DL, Schrier WH, Busch H. Immunoelectron microscopic localization of snRNPs. Biol Cell. 1983;49(1):1–10. [PubMed]
  • Spector DL, Fu XD, Maniatis T. Associations between distinct pre-mRNA splicing components and the cell nucleus. EMBO J. 1991 Nov;10(11):3467–3481. [PMC free article] [PubMed]
  • Trask BJ, Massa H, Kenwrick S, Gitschier J. Mapping of human chromosome Xq28 by two-color fluorescence in situ hybridization of DNA sequences to interphase cell nuclei. Am J Hum Genet. 1991 Jan;48(1):1–15. [PMC free article] [PubMed]
  • Visa N, Puvion-Dutilleul F, Harper F, Bachellerie JP, Puvion E. Intranuclear distribution of poly(A) RNA determined by electron microscope in situ hybridization. Exp Cell Res. 1993 Sep;208(1):19–34. [PubMed]
  • Walton TH, Moen PT, Jr, Fox E, Bodnar JW. Interactions of minute virus of mice and adenovirus with host nucleoli. J Virol. 1989 Sep;63(9):3651–3660. [PMC free article] [PubMed]
  • Wang J, Cao LG, Wang YL, Pederson T. Localization of pre-messenger RNA at discrete nuclear sites. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7391–7395. [PMC free article] [PubMed]
  • Wansink DG, Schul W, van der Kraan I, van Steensel B, van Driel R, de Jong L. Fluorescent labeling of nascent RNA reveals transcription by RNA polymerase II in domains scattered throughout the nucleus. J Cell Biol. 1993 Jul;122(2):283–293. [PMC free article] [PubMed]
  • Wiegant J, Kalle W, Mullenders L, Brookes S, Hoovers JM, Dauwerse JG, van Ommen GJ, Raap AK. High-resolution in situ hybridization using DNA halo preparations. Hum Mol Genet. 1992 Nov;1(8):587–591. [PubMed]
  • Xing Y, Lawrence JB. Nuclear RNA tracks: structural basis for transcription and splicing? Trends Cell Biol. 1993 Oct;3(10):346–353. [PubMed]
  • Xing Y, Johnson CV, Dobner PR, Lawrence JB. Higher level organization of individual gene transcription and RNA splicing. Science. 1993 Feb 26;259(5099):1326–1330. [PubMed]
  • Zachar Z, Kramer J, Mims IP, Bingham PM. Evidence for channeled diffusion of pre-mRNAs during nuclear RNA transport in metazoans. J Cell Biol. 1993 May;121(4):729–742. [PMC free article] [PubMed]
  • Zhang G, Taneja KL, Singer RH, Green MR. Localization of pre-mRNA splicing in mammalian nuclei. Nature. 1994 Dec 22;372(6508):809–812. [PubMed]
  • Zirbel RM, Mathieu UR, Kurz A, Cremer T, Lichter P. Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries. Chromosome Res. 1993 Jul;1(2):93–106. [PubMed]

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