Gene Regulation in Development and Disease
The Underhill laboratory is interested in understanding how aberrant gene regulation contributes to birth defects and cancer through the study of two overlapping model systems. In the first case, we study the essential developmental transcription factor Pax3. Mutations in the PAX3 gene occur in the mouse mutant Splotch and human Waardenburg syndrome, and are characterized by neural tube defects, sensorineural deafness and pigmentary disturbances, as well as craniofacial defects and reductions in limb musculature. From a gain-of-function standpoint, PAX3 is involved in a causative translocation in alveolar rhabdomyosarcoma and is often deregulated in neural crest-derived cancers, most notably in melanoma. As a result, the characterization of Pax3 provides an opportunity to understand the role of PAX genes in human congenital disease and lineage restricted malignancy, as well as their regulation of cellular differentiation. We are currently studying how Pax3 functions in the context of the nucleus using a number of cytological and molecular techniques. Our second project involves characterizing histone modifications during development and in cancer. The four core histones (H2A, H2B, H3, and H4) undergo a range of post-translational modifications—amongst these, we are most interested in methylation of histone H4. This modification is dynamic during cell differentiation and its accumulation is frequently disrupted in malignancy. We are currently using embryonic muscle development as a model to understand how histone H4 methylation regulates the balance between cell division and differentiation.
Technologies used: Molecular biology, Genetics, Biochemistry, Cell Imaging, and Bioinformatics
Goping IS, Sawchuk T, Underhill DA, and Bleackley RC (2006) Identification of -tubulin as a granzyme B-substrate during CTL-mediated apoptosis. J Cell Sci. 119:858-865.
Heit R, Underhill DA, Chan C, and Hendzel MJ (2006) Epigenetic regulation of centromere formation and kinetochore function. Biochem Cell Biol. 84:617-630.
McManus K, Biron VL, Heit R, Underhill DA, and Hendzel MJ. (2006) Histone H3 lysine 9 trimethylation is dynamic during mitosis and functions in chromosome congression and segregation. J Biol Chem. 281:8888-8897. *Selected as MUST READ in Faculty of 1000.
Berry FB, Lines MA, Oas JM, Footz T, Underhill DA, Gage PJ, and Walter MA (2006) Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Molec Genet. 15:905-919.
Corry GN and Underhill DA (2005) Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations. Pigment Cell Res. 18:427-438.
Corry GN and Underhill DA (2005) Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression. Biochem Cell Biol. 83:535-547.
Biron, VL, McManus K, Hu, N, Hendzel, MJ, and Underhill DA (2004) Distinct dynamics and distribution of histone methyl-lysine derivatives during mouse development. Dev Biol. 276:337-351. *Selected as OF SPECIAL INTEREST in Lin & Dent (2006) Curr Op Genet Dev. 16:137.
Kibar Z, Underhill DA, Canonne-Hergaux F, Gauthier S, Justice MJ, and Gros P (2001) Identification of a new chemically induced allele (Lpm1Jus) at the loop-tail locus: morphology, histology, and genetic mapping. Genomics. 72:331-337.
Kibar Z, Vogan KJ, Groulx N, Justice MJ, Underhill DA, and Gros P (2001) Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nat Genet. 28:251-255. *Selected as RECOMMENDED by Faculty of 1000.
Underhill DA (2000) Genetic and biochemical diversity in the Pax gene family. Biochem Cell Biol. 78:629-638.