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Nora I. Engel, PhD
Assistant Professor, Fels Institute for Cancer Research and Molecular Biology Assistant Professor, Biochemistry Telephone: 215-707-7611 Fax: 215-707-7536 Email: noraengel@temple.edu
Department of BiochemistryFels Institute for Cancer Research and Molecular Biology
My research concentrates on understanding the regulation of genomic imprinting.
Fertilization in mammals brings together one set of chromosomes from the sperm and one set of chromosomes from the oocyte. Thus, there are two copies for every gene. Most genes have the potential to be expressed from both the maternal and paternal copies. However, there is a group of genes with an unusual behavior: these genes are consistently expressed from only one of the two parental copies. It is believed that imprinted genes are marked with a memory of their parental origin, and that the marks are reversible chemical or structural modifications of the DNA occurring during development of each germline. This type of modification is termed “epigenetic”. Genomic imprinting is the process by which genes are labeled epigenetically as paternal or maternal, allowing them to be distinguished during development. The fact that imprinted genes are only active from one allele means that any perturbation in their expression is dominant. In fact, proper regulation of imprinted genes is crucial and alteration of their status in humans can lead to both genetic diseases and cancer.
To date, approximately 80 imprinted genes have been mapped in both humans and mice. Imprinted genes are found in clusters, suggesting regulatory mechanisms that can act over long genomic distances. One common feature of these clusters is the presence of regions of DNA that have been methylated in only one gamete and that are kept methylated on one parental chromosome. These differentially methylated regions, or DMRs, have been shown to have regulatory functions by targeted mutations. Proper regulation of imprinted genes is crucial, since they are functionally haploid, and alteration of their status in humans can lead to both genetic diseases and cancer.
The research in my lab explores the molecular mechanisms that regulate genomic imprinting by using gene targeting and transgenic technologies in mice to generate mutations designed to disrupt imprinting. This strategy allows us to elucidate the cis-acting sequences important for establishment and maintenance of imprinting.
We are focusing on the Cdkn1c domain, a complex group of imprinted genes including at least 8 maternally expressed genes, one paternally expressed non-coding RNA, and several embedded genes that escape imprinting and are expressed biallelically. Alterations of imprinting in this domain have been found in Beckwith-Wiedemann syndrome, an overgrowth disorder with predisposition to cancer. Also, mutations in Cdkn1c, a cyclin-dependent kinase inhibitor, have been documented in human cancers. We are using the mouse as a model system to identify and characterize mechanisms that regulate gene expression and imprinting in this region.
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