Ovarian Cancer Institute

Biomarkers capable of detecting andtargeting epithelial ovariancancer cells for diagnostics and therapeutics would be extremely valuable.Ovarian cancer is the deadliest reproductive malignancy among womenin the U.S., killing over 14 000 women each year. Both thelack of presenting symptoms and high mortality rates illustrate theneed for earlier diagnosis and improved treatment of this disease.The glycosyltransferase enzyme GnT-III encoded by the Mgat3 gene is responsible for the addition of GlcNAc (N-acetylglucosamine) to form bisecting N-linked glycan structures.GnT-III mRNA expression is amplified in ovarian cancer tissues comparedwith normal ovarian tissue. We use a lectin capture strategy coupledto nano-ESI–RPLC–MS/MS to isolate and identify the membraneglycoproteins and unique glycan structures associated with GnT-IIIamplification in human ovarian cancer tissues. Our data illustratethat the majority of membrane glycoproteins with bisecting glycosylationare common to both serous and endometrioid histological subtypes ofovarian cancer, and several have been reported to participate in signalingpathways such as Notch, Wnt, and TGFβ.

Experimentally characterized enhancer regions have previously been shown to display specific patterns of enrichment for several different histone modifications. We modelled these enhancer chromatin profiles in the human genome and used them to guide the search for novel enhancers derived from transposable element (TE) sequences. To do this, a computational approach was taken to analyze the genome-wide histone modification landscape characterized by the ENCODE project in two human hematopoietic cell types, GM12878 and K562. We predicted the locations of 2,107 and 1,448 TE-derived enhancers in the GM12878 and K562 cell lines respectively. A vast majority of these putative enhancers are unique to each cell line; only 3.5% of the TE-derived enhancers are shared between the two. We evaluated the functional effect of TE-derived enhancers by associating them with the cell-type specific expression of nearby genes, and found that the number of TE-derived enhancers is strongly positively correlated with the expression of nearby genes in each cell line. Furthermore, genes that are differentially expressed between the two cell lines also possess a divergent number of TE-derived enhancers in their vicinity. As such, genes that are up-regulated in the GM12878 cell line and down-regulated in K562 have significantly more TE-derived enhancers in their vicinity in the GM12878 cell line and vice versa. These data indicate that human TE-derived sequences are likely to be involved in regulating cell-type specific gene expression on a broad scale and suggest that the enhancer activity of TE-derived sequences is mediated by epigenetic regulatory mechanisms.