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CTCF Binding at the Insulin-Like Growth Factor-II (IGF2)/H19 Imprinting Control Region Is Insufficient to Regulate IGF2/H19 Expression in Human Tissues

Medical Service, Veterans Affairs Palo Alto Health Care System, and Department of Medicine, Stanford University, Palo Alto, California 94304

Address all correspondence and requests for reprints to: Andrew Hoffman, Medical Service, Veterans Affairs Palo Alto Medical Center, 3801 Miranda Avenue, Palo Alto, California 94304. E-mail: arhoffman{at}stanford.edu.

The adjacent IGF2 and H19 genes are imprinted in most normal mouse and human tissues, but imprinting is often lost in tumors. Mouse models suggest that parental-allele specific CCCTC-binding factor (CTCF) binding at the IGF2/H19 imprinting control region (ICR) regulates the expression of these two genes. Using chromatin immunoprecipitation and PCR, we show that in several normal and neoplastic human tissues, CTCF consistently binds unmethylated ICR elements, but CTCF binding does not result in predictable gene expression. In the fetal brain, CTCF binding is monoallelic and specific for the unmethylated ICR, yet IGF2/H19 expression is biallelic. In osteosarcoma tumors, aberrant methylation of the IGF2/H19 ICR results in equally aberrant CTCF binding, yet expression of these genes does not correlate with CTCF binding. This is the first description of chromatin immunoprecipitation for CTCF binding at the human IGF2/H19 ICR, and the results demonstrate that CTCF binding at the IGF2/H19 ICR is insufficient to regulate the expression of IGF2/H19 in many human tissues.

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