Distinguished Service Professor, Departments of Biochemistry & Molecular Biology and Molecular and Human Genetics; Programs in Cell & Molecular Biology, Structural, Computational Biology, and Molecular Biophysics, and Translational Biology and Molecular Medicine

B.A., Wabash College, 1966
Ph.D., California Institute of Technology, 1971

RESEARCH INTERESTS:
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.

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SELECTED PUBLICATIONS:

1. Wilson JH (2008). Knockout punches with a fistful of zinc fingers. Proc. Natl. Acad. Sci. USA. 105: 5653-5654.

2. Dion V, Lin Y, Hubert L Jr, Waterland RA, Wilson JH (2008). Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline. Hum. Mol. Genet. 17: 1306-1317.

3. Dion V, Lin Y, Price BA, Fyffe SL, Seluanov A, Gorbunova V, Wilson JH (2008). Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination. DNA Repair 7: 313-320.

4. Lin Y, Wilson JH (2007). Transcription-induced CAG repeat contraction in human cells is mediated in part by transcription-coupled nucleotide excision repair. Mol. Cell. Biol. 27: 6209-6217.

5. Lin Y, Dion V, Wilson JH (2006). Transcription promotes contraction of CAG repeat tracts in human cells. Nat. Struct. Mol. Biol. 13: 179-180.

6. Lin Y, Dion V, Wilson JH (2006). Transcription and triplet repeat instability” in Genetic Instabilities and Neurological Diseases, 2nd Edition, R.D. Wells & T. Ashizawa, eds., p 691-704.

7. Wensel TG, Gross AK, Chan F, Sykoudis K, Wilson JH (2005). Rhodopsin-EGFP Knockins for Imaging Quantal Gene Alterations. Vision Res. 45: 3445-3453.

8. Gorbunova V, Seluanov A, Mittelman D, Wilson JH (2004). Genome-wide demethylation destabilizes CTG•CAG trinucleotide repeats in mammalian cells. Hum. Mol. Genet. 13: 2979-2989.

9. Chan F, Bradley A, Wensel TG, Wilson JH (2004). Knock-in human rhodopsin-GFP fusions as mouse models for human disease and targets for gene therapy. Proc. Natl. Acad. Sci. USA 101: 9109-9114.

For more publications, see listing on Pub Med.

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CONTACT INFORMATION:
John H. Wilson, Ph.D.
Department of Biochemistry & Molecular Biology
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030, U.S.A.

Telephone: 713-798-5760
Fax: 713-796-9438
E-mail:

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