Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1997 Jul 1;25(13):2589–2594. doi: 10.1093/nar/25.13.2589

The POU-domain factor Brn-3.0 recognizes characteristic sites in the herpes simplex virus genome.

E E Turner 1, J M Rhee 1, L T Feldman 1
PMCID: PMC146794  PMID: 9185568

Abstract

The restriction of herpes virus latency to mammalian sensory ganglia has led to a search for tissue-specific regulatory molecules in these neurons which alter viral gene expression. We have recently shown that the POU-domain transcriptional regulator Brn-3.0 is abundantly expressed in the adult trigeminal ganglion. To begin to examine the hypothesis that Brn-3.0 might participate in the regulation of the HSV life-cycle, we used Brn-3.0 POU-domain protein as an affinity matrix, and biochemically screened the entire HSV genome for sites of Brn-3.0 binding. This screen identified several sites of the form TA/TA A T N A N TA/T, which significantly do not include the previously identified HSV octamer sequences. All of the selected sites occur in the <25% of the HSV genome which has not been assigned to open reading frames, suggesting that these sites may be transcriptional regulatory elements recognized by Brn-3.0 or another homeobox factor with similar DNA binding properties. However, these sites do not interact with Brn-3.0 with sufficiently high affinity to directly mediate transcriptional activation by Brn-3.0 alone in transfection assays. The experiments described also provide an effective general method for exhaustive screening of large viral genomes or sub-genomic fragments of eukaryotic DNA for sites of interaction with specific transcription factors.

Full Text

The Full Text of this article is available as a PDF (156.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Dobson A. T., Sederati F., Devi-Rao G., Flanagan W. M., Farrell M. J., Stevens J. G., Wagner E. K., Feldman L. T. Identification of the latency-associated transcript promoter by expression of rabbit beta-globin mRNA in mouse sensory nerve ganglia latently infected with a recombinant herpes simplex virus. J Virol. 1989 Sep;63(9):3844–3851. doi: 10.1128/jvi.63.9.3844-3851.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Fedtsova N. G., Turner E. E. Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors. Mech Dev. 1995 Nov;53(3):291–304. doi: 10.1016/0925-4773(95)00435-1. [DOI] [PubMed] [Google Scholar]
  3. Gerrero M. R., McEvilly R. J., Turner E., Lin C. R., O'Connell S., Jenne K. J., Hobbs M. V., Rosenfeld M. G. Brn-3.0: a POU-domain protein expressed in the sensory, immune, and endocrine systems that functions on elements distinct from known octamer motifs. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10841–10845. doi: 10.1073/pnas.90.22.10841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gerster T., Roeder R. G. A herpesvirus trans-activating protein interacts with transcription factor OTF-1 and other cellular proteins. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6347–6351. doi: 10.1073/pnas.85.17.6347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gruber C. A., Rhee J. M., Gleiberman A., Turner E. E. POU domain factors of the Brn-3 class recognize functional DNA elements which are distinctive, symmetrical, and highly conserved in evolution. Mol Cell Biol. 1997 May;17(5):2391–2400. doi: 10.1128/mcb.17.5.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hagmann M., Georgiev O., Schaffner W., Douville P. Transcription factors interacting with herpes simplex virus alpha gene promoters in sensory neurons. Nucleic Acids Res. 1995 Dec 25;23(24):4978–4985. doi: 10.1093/nar/23.24.4978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. He X., Treacy M. N., Simmons D. M., Ingraham H. A., Swanson L. W., Rosenfeld M. G. Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature. 1989 Jul 6;340(6228):35–41. doi: 10.1038/340035a0. [DOI] [PubMed] [Google Scholar]
  8. Kemp L. M., Dent C. L., Latchman D. S. Octamer motif mediates transcriptional repression of HSV immediate-early genes and octamer-containing cellular promoters in neuronal cells. Neuron. 1990 Feb;4(2):215–222. doi: 10.1016/0896-6273(90)90096-x. [DOI] [PubMed] [Google Scholar]
  9. Kristie T. M., Sharp P. A. Interactions of the Oct-1 POU subdomains with specific DNA sequences and with the HSV alpha-trans-activator protein. Genes Dev. 1990 Dec;4(12B):2383–2396. doi: 10.1101/gad.4.12b.2383. [DOI] [PubMed] [Google Scholar]
  10. Lillycrop K. A., Dawson S. J., Estridge J. K., Gerster T., Matthias P., Latchman D. S. Repression of a herpes simplex virus immediate-early promoter by the Oct-2 transcription factor is dependent on an inhibitory region at the N terminus of the protein. Mol Cell Biol. 1994 Nov;14(11):7633–7642. doi: 10.1128/mcb.14.11.7633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lillycrop K. A., Dent C. L., Wheatley S. C., Beech M. N., Ninkina N. N., Wood J. N., Latchman D. S. The octamer-binding protein Oct-2 represses HSV immediate-early genes in cell lines derived from latently infectable sensory neurons. Neuron. 1991 Sep;7(3):381–390. doi: 10.1016/0896-6273(91)90290-g. [DOI] [PubMed] [Google Scholar]
  12. Lillycrop K. A., Estridge J. K., Latchman D. S. Functional interaction between different isoforms of the Oct-2 transcription factor expressed in neuronal cells. Biochem J. 1994 Feb 15;298(Pt 1):245–248. doi: 10.1042/bj2980245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lillycrop K. A., Estridge J. K., Latchman D. S. The octamer binding protein Oct-2 inhibits transactivation of the herpes simplex virus immediate-early genes by the virion protein Vmw65. Virology. 1993 Oct;196(2):888–891. doi: 10.1006/viro.1993.1552. [DOI] [PubMed] [Google Scholar]
  14. Lillycrop K. A., Howard M. K., Estridge J. K., Latchman D. S. Inhibition of herpes simplex virus infection by ectopic expression of neuronal splice variants of the Oct-2 transcription factor. Nucleic Acids Res. 1994 Mar 11;22(5):815–820. doi: 10.1093/nar/22.5.815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lillycrop K. A., Latchman D. S. Alternative splicing of the Oct-2 transcription factor RNA is differentially regulated in neuronal cells and B cells and results in protein isoforms with opposite effects on the activity of octamer/TAATGARAT-containing promoters. J Biol Chem. 1992 Dec 15;267(35):24960–24965. [PubMed] [Google Scholar]
  16. McEvilly R. J., Erkman L., Luo L., Sawchenko P. E., Ryan A. F., Rosenfeld M. G. Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons. Nature. 1996 Dec 12;384(6609):574–577. doi: 10.1038/384574a0. [DOI] [PubMed] [Google Scholar]
  17. McGeoch D. J., Dalrymple M. A., Davison A. J., Dolan A., Frame M. C., McNab D., Perry L. J., Scott J. E., Taylor P. The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1. J Gen Virol. 1988 Jul;69(Pt 7):1531–1574. doi: 10.1099/0022-1317-69-7-1531. [DOI] [PubMed] [Google Scholar]
  18. McKnight J. L., Kristie T. M., Roizman B. Binding of the virion protein mediating alpha gene induction in herpes simplex virus 1-infected cells to its cis site requires cellular proteins. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7061–7065. doi: 10.1073/pnas.84.20.7061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. O'Hare P., Goding C. R. Herpes simplex virus regulatory elements and the immunoglobulin octamer domain bind a common factor and are both targets for virion transactivation. Cell. 1988 Feb 12;52(3):435–445. doi: 10.1016/s0092-8674(88)80036-9. [DOI] [PubMed] [Google Scholar]
  20. Poellinger L., Roeder R. G. Octamer transcription factors 1 and 2 each bind to two different functional elements in the immunoglobulin heavy-chain promoter. Mol Cell Biol. 1989 Feb;9(2):747–756. doi: 10.1128/mcb.9.2.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Preston C. M., Frame M. C., Campbell M. E. A complex formed between cell components and an HSV structural polypeptide binds to a viral immediate early gene regulatory DNA sequence. Cell. 1988 Feb 12;52(3):425–434. doi: 10.1016/s0092-8674(88)80035-7. [DOI] [PubMed] [Google Scholar]
  22. Stern S., Tanaka M., Herr W. The Oct-1 homoeodomain directs formation of a multiprotein-DNA complex with the HSV transactivator VP16. Nature. 1989 Oct 19;341(6243):624–630. doi: 10.1038/341624a0. [DOI] [PubMed] [Google Scholar]
  23. Stevens J. G., Wagner E. K., Devi-Rao G. B., Cook M. L., Feldman L. T. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science. 1987 Feb 27;235(4792):1056–1059. doi: 10.1126/science.2434993. [DOI] [PubMed] [Google Scholar]
  24. Turner E. E., Fedtsova N., Rosenfeld M. G. POU-domain factor expression in the trigeminal ganglion and implications for herpes virus regulation. Neuroreport. 1996 Nov 25;7(18):2829–2832. doi: 10.1097/00001756-199611250-00003. [DOI] [PubMed] [Google Scholar]
  25. Turner E. E., Jenne K. J., Rosenfeld M. G. Brn-3.2: a Brn-3-related transcription factor with distinctive central nervous system expression and regulation by retinoic acid. Neuron. 1994 Jan;12(1):205–218. doi: 10.1016/0896-6273(94)90164-3. [DOI] [PubMed] [Google Scholar]
  26. Valyi-Nagy T., Deshmane S. L., Spivack J. G., Steiner I., Ace C. I., Preston C. M., Fraser N. W. Investigation of herpes simplex virus type 1 (HSV-1) gene expression and DNA synthesis during the establishment of latent infection by an HSV-1 mutant, in1814, that does not replicate in mouse trigeminal ganglia. J Gen Virol. 1991 Mar;72(Pt 3):641–649. doi: 10.1099/0022-1317-72-3-641. [DOI] [PubMed] [Google Scholar]
  27. Wheatley S. C., Kemp L. M., Wood J. N., Latchman D. S. Cell lines derived from dorsal root ganglion neurons are nonpermissive for HSV and express only the latency-associated transcript following infection. Exp Cell Res. 1990 Oct;190(2):243–246. doi: 10.1016/0014-4827(90)90192-d. [DOI] [PubMed] [Google Scholar]
  28. Wood J. N., Lillycrop K. A., Dent C. L., Ninkina N. N., Beech M. M., Willoughby J. J., Winter J., Latchman D. S. Regulation of expression of the neuronal POU protein Oct-2 by nerve growth factor. J Biol Chem. 1992 Sep 5;267(25):17787–17791. [PubMed] [Google Scholar]
  29. Xiang M., Gan L., Zhou L., Klein W. H., Nathans J. Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11950–11955. doi: 10.1073/pnas.93.21.11950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Xiang M., Zhou L., Macke J. P., Yoshioka T., Hendry S. H., Eddy R. L., Shows T. B., Nathans J. The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J Neurosci. 1995 Jul;15(7 Pt 1):4762–4785. doi: 10.1523/JNEUROSCI.15-07-04762.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Xiang M., Zhou L., Peng Y. W., Eddy R. L., Shows T. B., Nathans J. Brn-3b: a POU domain gene expressed in a subset of retinal ganglion cells. Neuron. 1993 Oct;11(4):689–701. doi: 10.1016/0896-6273(93)90079-7. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES