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IMBS

Houston, Texas

CMB research is conducted at Baylor College of Medicine in the Texas Medical Center, Houston.
Integrative Molecular and Biomedical Sciences Graduate Program
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John H. Wilson, Ph.D.

Professor, Department of Molecular & Human Genetics
and Department of Biochemistry & Molecular Biology
AB, Wabash College, 1966
PhD, California Institute of Technology

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 have recently demonstrated that we can efficiently introduce double-strand breaks into the rhodopsin gene in rod cells in mice. These breaks can be repaired by both homologous recombination (HR) and nonhomologous end joining (NHEJ), demonstrating for the first time that these DNA repair process operate effectively in terminally differentiated rod cell neurons. Remarkably, we have shown that we can induce HR-mediated gene correction in about 15% of treated cells.

Selected Publications:

Mittelman, D., Moye, C., Morton, J., Sykoudis, K., Lin, Y., Carroll, D., and Wilson, J.H. (2009) Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells. Proc. Natl. Acad. Sci. USA. 106:9607-9612. PMID: 19482946

Dion, V., and Wilson, J.H. (2009) Instability and chromatin structure of expanded trinucleotide repeats. Trends in Genetics. 25:288-297. PMID: 19540013

Lin, Y.L., and Wilson, J.H. (2009) Diverse effects of individual mismatch repair components on transcription-induced CAG repeat instability in human cells. DNA Repair 8:878-885. PMID: 19497791

Lin, Y, Hubert, L Jr, Wilson, J.H. (2009) Transcription destabilizes triplet repeats. Mol. Carcinog. 48:350-361. PMID: 18973172

Wilson, J.H. (2008) Knockout punches with a fistful of zinc fingers. Proc. Natl. Acad. Sci. USA 105:5653-5654. PMID: 18401029

Dion, V., Lin, Y., Hubert, L., Waterland, R.A., and Wilson, J.H. (2008) Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline. Hum. Mol. Genet. 17:1306-1317. PMID: 18252747

Dion, V., Lin, Y., Price, B.A., Fyffe, S.L., Seluanov, A., Gorbunova, V., and Wilson, J.H. (2008) Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination. DNA Repair 7:313-320. PMID: 18083071

Lin, Y., and Wilson, J.H. (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. PMID: 17591697

Lin, Y., Dion, V., and Wilson, J.H. (2006) Transcription promotes contraction of CAG repeat tracts in human cells. Nat. Struct. Mol. Biol. 13:179-180. PMID: 16388310

Wensel, T.G., Gross, A.K., Chan, F., Sykoudis, K., and Wilson, J.H. (2005) Rhodopsin-EGFP Knockins for Imaging Quantal Gene Alterations. Vision Res. 45:3445-3453. PMID: 16139321

Chan, F., Bradley, A., Wensel, T.G., and Wilson, J.H. (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. PMID: 15184660


For more publications, see listing on PubMed.

Contact Information:

Dr. John H. Wilson
Department of Biochemistry & Molecular Biology
Baylor College of Medicine
One Baylor Plaza Houston, TX 77030, U.S.A
Telephone: (713) 798-5760
Fax: (713) 796-9438
E-mail: jwilson@bcm.edu


Updated: 11/09

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