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Department of Biochemistry and Molecular Biology

Houston, Texas

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Verna and Marrs McLean Department of Biochemistry and Molecular Biology
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John H. Wilson, Ph.D.

John H. Wilson, Ph.D.

Distinguished Service Professor
Department of Biochemistry and Molecular Biology
Department of Molecular and Human Genetics

Director of Graduate Studies

Education and Awards

  • Ph.D., Biochemistry/Genetics, 1972, California Institute of Technology
  • Postdoctoral, Molecular Biology, 1973, Stanford University
  • 1975-1980, Research Career Development Award, National Institutes of Health

Targeted Genome Modification

My laboratory is interested in two, complementary aspects of genome biology in mammalian cells: defining the pathways that normally guarantee genome integrity, and manipulating those pathways to accomplish precise modifications for gene therapy. We are exploring these interests in the context of two inherited human neurological diseases: myotonic dystrophy and retinitis pigmentosa.

Myotonic dystrophy (DM) is one of a growing number of human neurological diseases that are caused by the intergenerational expansion of trinucleotide (triplet) repeats. Like other repeats, the CTG/CAG triplet repeat responsible for DM is unstable because it tends to form secondary structures —hairpins and slipped-strand structures —that interfere with DNA metabolism, leading to repeat expansion and disease. We have developed exquisitely sensitive assays that use the selectable APRT and HPRT genes to detect repeat instability in mammalian cells. These assays reveal that CTG/CAG triplet repeats are only mildly destabilized by replication —the principal cause of instability in bacteria and yeast —but are dramatically destabilized by transcription through the repeat and by genome-wide demethylation. Notably, in human patients triplet repeats are extremely unstable during gametogenesis and early embryogenesis, precisely those times when the genome in undergoing substantial changes in DNA methylation. Also, triplet repeats are commonly unstable in non-dividing cells, where transcription —but not replication —might play a key role. We are exploring the pathways for transcription-induced and demethylation-induced instability using RNAi technology in cells and genetic approaches in mice.

Retinitis pigmentosa (RP), which affects 1/3000 people worldwide, begins with loss of peripheral vision in the teens and progresses over the next 30 years, or so, to tunnel vision and blindness. We are developing gene-specific strategies for genome modification, with the ultimate aim of treating this disease in humans. Dominant mutations in the rhodopsin gene, which encodes the photopigment in rod photoreceptors, are the largest single cause of RP. To develop treatment protocols, we initially constructed a mouse model by replacing the mouse rhodopsin gene with the human gene fused to GFP. Human rhodopsin-GFP is expressed normally in mouse rod cells and provides a convenient color marker for ready assessment of treatment efficacy. We have now generated additional mouse lines, each of which carries a mutant human rhodopsin-GFP gene that prevents expression of GFP, allowing us to detect gene correction by the appearance of green fluorescence in an otherwise black retina. Using such modified animals, we are testing various gene specific treatments, including zinc-finger nucleases and interfering RNA, for their ability to correct or knockout defective genes, or to decrease their transcription. These studies will also elucidate the DNA repair capabilities of terminally differentiated neurons, which are currently undefined.

Low dose electron micrograph of a double-shelled rotavirus embedded in vitreous ice.

Albino mouse with one rhodopsin gene replaced by a human rhodopsin-GFP fusion gene

Selected Publications

  • Price, B.A., Sandoval, I.M., Chan, F., Simons, D.L., Wu, S.M., Wensel, T.G., and Wilson, J.H. (2011) Mislocalization and degradation of human P23H-rhodopsin-GFP in a knock-in mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 52:9728-9736.
  • Chan, F., Hauswirth, W.W., Wensel, T.G., and Wilson, J.H. (2011) Efficient mutagenesis of the rhodopsin gene in rod photoreceptor neurons in mice. Nucleic Acids Res. 39:5955-5966.
  • Hubert, L. Jr., Lin, Y., Dion, V., and Wilson, J.H. (2011) Topoisomerase 1 and single-strand break repair modulate transcription-induced CAG repeat contraction in human cells. Mol. Cell. Biol.15:3105-3112.
  • Lin, Y. and Wilson, J.H. (2011) Transcription-induced DNA toxicity at trinucleotide repeats: Double bubble is trouble Cell Cycle 10:611-618.
  • Lin Y, Leng M, Wan M, Wilson JH (2010). Convergent transcription through a long CAG tract destabilizes repeats and induces apoptosis. Mol. Cell Biol. 30(18): 4435-51.
  • Mittelman D, Wilson JH (2010). Stress, genomes, and evolution. Cell Stress Chaperones 15(5): 463-6.
  • Mittelman D, Sykoudis K, Hersh M, Lin Y, Wilson JH (2010). Hsp90 modulates CAG repeat instability in human cells. Cell Stress Chaperones 15(5): 753-9.
  • Lin Y, Dent SY, Wilson JH, Wells RD, Napierala M (2010). R-loops stimulate genetic instability of CTG.CAG repeats. Proc. Natl. Acad. Sci. USA 107(2): 692-7.
  • Mittelman D, Moye C, Morton J, Sykoudis K, Lin Y, Carroll D, Wilson JH (2009). Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells. Proc. Natl. Acad. Sci. USA 106(24): 9607-12.
  • Dion V, Wilson JH (2009). Instability and chromatin structure of expanded trinucleotide repeats. Trends Genet. 25(7): 288-97.

View more articles published by Dr. Wilson.

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