Benjamin Tycko, MD, PhD

Molecular Biology of Genomic Imprinting.	Molecular Genetics of Alzheimer's Disease.

One aspect of our research concerns the mechanisms and consequences of genomic imprinting, with a particular interest in the role of this phenomenon in human tumorigenesis. Imprinting is a non-Mendelian form of epigenetic gene regulation in which there is selective transcriptional silencing of particular genes on one parental allele. We are interested in the possibility that human chromosome 11p15 may contain one or more paternally imprinted tumor suppressor genes whose monoallelic loss or activation may be an early step in the formation of several types of childhood tumors, including Wilms' tumor (WT) of the kidney. That this might be the case was originally suggested by the finding of highly selective loss of maternal chromosome 11p15 alleles in WTs. Work from our laboratory and others has shown that at least three imprinted genes on chromosome 11p15 are systematically altered in their expression in WTs; the maternally expressed H19 gene is frequently silenced and the paternally expressed IGF2 gene becomes biallelically active; while the maternally expressed p57KIP2 gene is variably down-regulated. At least for H19, which encodes a non-translated RNA with growth-suppressive activity in some tumor cell lines, the epigenetic silencing (a "gain of imprinting" on the previously active maternal allele) is a very early event in tumorigenesis since it is sometimes present in preneoplastic cells adjacent to WTs. Our work has also dealt with the regionality of imprinting along the chromosome -- it is now clear that there is a very large imprinted domain containing multiple genes with activities regulating cell and tissue growth. We are identifying these genes, most recently IPL and IMPT1, to learn more about the biological and evolutionary rationale for imprinting.

Another area of interest in our laboratory is the genetics of neurodegeneration in Alzheimer's disease (AD). In collaboration with R. Mayeux in the Sergievsky Center at Columbia, we have studied the association of particular alleles of the ApoE gene and flanking genes on chromosome 19 with AD in a large community-based survey of elderly subjects from three different ethnic groups. In this study we hope to clarify the genetic basis for the association of the ApoE4 allele with increased risk of developing AD. An area of future research may be functional studies of ApoE and other AD-related genes.

Selected Publications:

• Zhang, Y., and Tycko, B. Monoallelic expression of the human H19 gene. Nature Genet. 1: 40-44 (1992).

• Hao, Y., Crenshaw, T., Moulton, T., Newcomb, E, and Tycko, B. Tumor suppressor activity of H19 RNA. Nature 365: 764-767 (1993).

• Moulton, T., Crenshaw, T., Hao, Y., Moosikasuwan, J., Lin, N., Dembitzer, F., Hensle, T., Weiss, L., McMorrow, L., Loew, T., Kraus, W., Gerald, W., and Tycko, B. Epigenetic lesions at the H19 locus in Wilms' tumor patients. Nature Genet. 7: 440-447 (1994).

• Maestre, G., Stern, Y., Ottman, R., Gurland, B., Tang. M.-X., Chun, M., Shelanski, M., Tycko, B., and Mayeux, R. Apolipoprotein-E and Alzheimer's diseases: Ethnic variation in genotypic risks. Ann. Neurol. 37: 254-259 (1995).

• Chung, W.-Y., Yuan, L., Feng, L., Hensle, T., and Tycko, B. Chromosome 11p15.5 regional imprinting: comparative analysis of KIP2 and H19 in human tissues and Wilms' tumors. Hum. Mol. Genet. 5: 1101-1108 (1996).

• Tycko, B., Feng, L., Nguyen, L., Francis, A., Hays, A., Chung, W.-Y., Tang, M.-X., Stern, Y., Sahota, A., Hendrie, H., and Mayeux, R. Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer's disease. Hum. Genet. 98: 430-436 (1996).

• Yuan, L., Qian, N., Zhao, L., Feng, L., and Tycko, B. An extended region of biallelic gene expression and rodent-human synteny downstream of the imprinted H19 gene on chromosome 11p15.5. Hum. Mol. Genet. 5: 1931-1937 (1996).

• O'Keefe, D., Dao, D., Sanderson, R., Weiss, L., Warburton, D., Yeboa, K., and Tycko, B. Coding mutations in p57KIP2 occur in some cases of Beckwith-Weidemann syndrome but are rare or absent in Wilms' tumors. Am. J. Hum. Genet. 61: 295-303 (1997).

• Qian, N., Frank, D., O'Keefe, D., Dao, D., Zhao, L., Yuan, L., Wang, Q., Keating, M., Walsh, C., and Tycko, B. The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is similar to TDAG51, implicated in Fas expression and apoptosis. Hum. Mol. Genet. 6: 2021-2029 (1997).

• Dao, D., Frank, D., Qian, N., O'Keefe, D., Vosatka, R.J., Walsh, C.P., and Tycko, B. IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes. Hum. Mol. Genet. 7: 597-608 (1998).

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Oct. 1998