John H. Wilson, Ph.D.
Professor of Molecular and Human Genetics
Distinguished Service Professor, Department of Biochemistry & Molecular Biology; Programs in Integrative Molecular and Biomedical Sciences; Structural and Computational Biology & Molecular Biophysics; and Translational Biology & Molecular Medicine
B.A., Wabash College, 1966
Ph.D., California Institute of Technology, 1971
We are interested in two, complementary aspects of genome biology: defining the pathways that control the stability of disease-causing trinucleotide repeats, and developing methods to accomplish precise gene modifications for gene therapy. We are exploring these interests in the context of inherited human neurological diseases.
Instability of Trinucleotide Repeats
Expansions of trinucleotide repeats in specific human genes cause several neurodegenerative diseases such as Huntington disease and myotonic dystrophy. The basis for repeat instability—their ability to expand and contract the number of repeats in a tract—is unclear. To define these mechanisms, we have developed exquisitely sensitive assays that detect repeat instability in mammalian cells. These assays reveal that CAG repeats are dramatically destabilized by transcription through the repeat, by genome-wide demethylation, and by environmental stresses such as hypoxia, heat shock, cold shock, and oxidative stress.
By knocking down expression of specific genes in human cells with siRNAs, and using gene mutations in mice, we are identifying the roles of various genes and DNA metabolic processes that are responsible for repeat instability. In addition, we are optimizing the use of zinc-finger nucleases that introduce double-strand breaks into CAG repeats, and zinc-finger nickases that introduce single strand breaks, as reagents to shrink long CAG tracts as a potential therapy for human patients.
Targeted Genome Modification
Retinitis pigmentosa (RP), which affects 1 in every 3000 people worldwide, typically begins with loss of peripheral vision in the teens and progresses to tunnel vision and blindness in middle age. 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 are the largest single cause of RP.
To develop treatment protocols, we have generated mouse models in which one copy of the mouse rhodopsin gene is replaced with one or another forms of the human rhodopsin gene fused to GFP. These fluorescently tagged mouse models provide convenient color markers for the assessment of treatment efficacy. We are using these mouse models to test and optimize various gene specific cleavage reagents such as zinc-finger nucleases for their ability to correct or knockout defective genes. These studies will also elucidate the DNA repair capabilities of terminally differentiated neurons, which are currently undefined.
- Chatterjee N, Santillan BA, Wilson JH (2013). Microsatellite Repeats: Canaries in the Coalmine. In Stress-Induced Mutagenesis, D. Mittelman, ed, (Springer Publishing Co, New York, NY) pp. 119-150.
- Mittelman D, Wilson JH (2013). The fractured genome of HeLa cells. Genome Biol. 14(4): 111. PubMed PMID: 23594443
- Price BA, Sandoval IM, Chan F, Nichols R, Roman-Sanchez R, Wensel TG, Wilson JH (2012). Rhodopsin gene expression determines rod outer segment size and rod cell resistance to a dominant-negative neurodegeneration mutant. PLoS One 7(11): e49889. PubMed PMID: 23185477
- Lin Y, Wilson JH (2012). Nucleotide excision repair, mismatch repair, and R-loops modulate convergent transcription-induced cell death and repeat instability. PLoS One 7(10): e46807. PubMed PMID: 23056461
- Price BA, Sandoval IM, Chan F, Simons DL, Wu SM, Wensel TG, Wilson JH (2011). Mislocalization and degradation of human P23H-rhodopsin-GFP in a knockin mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 52(13): 9728-36. PubMed PMID: 22110080
- Hubert L Jr, Lin Y, Dion V, Wilson JH (2011). Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Hum. Mol. Genet. 20(24): 4822-30. PubMed PMID: 21926083
- Chan F, Hauswirth WW, Wensel TG, Wilson JH (2011). Efficient mutagenesis of the rhodopsin gene in rod photoreceptor neurons in mice. Nucleic Acids Res. 39(14): 5955-66. PubMed PMID: 21478169
- Hubert L Jr, Lin Y, Dion V, Wilson JH (2011). Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells. Mol. Cell Biol. 31(15): 3105-12. PubMed PMID: 21628532
- Lin Y, Wilson JH (2011). Transcription-induced DNA toxicity at trinucleotide repeats: double bubble is trouble. Cell Cycle 10(4): 611-8. PubMed PMID: 21293182
- 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. PubMed PMID: 20647539
- Mittelman D, Wilson JH (2010). Stress, genomes, and evolution. Cell Stress Chaperones 15(5): 463-6. PubMed PMID: 20521130
- 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. PubMed PMID: 20373063
- Lin Y, Dent SY, Wilson JH, Wells RD, Napierala M (2010). R-loops stimulate genetic instability of CTG.CAG repeats. Proc. Natl. Acad. Sci. U S A 107(2): 692-7. PubMed PMID: 20080737
- 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. U S A 106(24): 9607-12. PubMed PMID: 19482946
- Dion V, Wilson JH (2009). Instability and chromatin structure of expanded trinucleotide repeats. Trends Genet. 25(7): 288-97. PubMed PMID: 19540013
John H. Wilson, Ph.D.
Department of Biochemistry & Molecular Biology
Baylor College of Medicine
One Baylor Plaza, MS BCM125
Houston, TX, 77030, U.S.A.