POTW: Uncovering the function of an intergenic SNP

My choice for Paper Of The Week this week is a report from a few weeks back (digging through the pile...) in which a polymorphism conferring increased risk of renal cell carcinoma is investigated for allele-specific functions. The paper is "Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression" by Schödel, et al. (Nature Genetics 44:420-425).

Although the authors had several clues that the risk SNPs would (likely) affect expression of CCND1 (cyclin D1) in a manner regulated by hypoxia-induced factors - namely, that HIFs were known to regulate CCND1 but from an unknown binding site and that CCND1 is an established oncogene, among others - they accumulated much new data to nail down the role of EPAS1 (HIF-2) in regulating CCND1 expression.

One nice aspect of this work is the authors' taking advantage of signals seen in a renal carcinoma cell line and not in a breast cancer cell line (serving then as control). For example, they looked at the epigenetic enhancer marks at the 11q13.3 susceptibility locus with FAIRE (ormaldehyde-assisted isolation of regulatory elements to identify regions of nucleosome occupancy), and EPAS1 binding as assessed by ChIP-qPCR. The use of pVHL-defective RCC cell lines verified the role of VHL (von Hippel–Lindau tumor suppressor) in this cancer and consequence of allele-specific expression of CCND1.

Taken together, the data presented show that the haplotype associating with reduced renal cell cancer risk hinders EPAS1 binding, "resulting in an allelic imbalance in cyclin D1 expression, thus affecting a link between hypoxia pathways and cell cycle control." This is nice work and a fine example of the approaches needed to develop a clear understanding of polymorphism and disease risk from a functional perspective.