Promoter histone H3K27 methylation in the control of IGF2 imprinting in human tumor cell lines

摘要

Aberrant imprinting of the insulin-like growth factor II (IGF2) gene is a molecular hallmark of many tumors. Reactivation of thenormally suppressed maternal allele leads to upregulation of the growth factor that promotes tumor growth. However, the mechanisms underlying the loss of imprinting (LOI) remain poorly defined. We examined the epigenotypes at the gene promoters that control IGF2 allelic expression. Using chromatin immunoprecipitation,wefound that in cells characterized by maintenance of IGF2 imprinting, three IGF2promoters were differentiallymodified, with the suppressed allele heavily methylated at histone H3K27 while the active allelewasunmethylated. In the LOI tumors,however, both alleleswere unmethylated,andcorrespondingly there wasnobinding of SUZ12, the docking factor of thepolycomb repressive complex 2 (PRC2),andof the zinc fingercontaining transcription factor (CTCF) that recruits the PRC2. Using chromatin conformation capture, we found that the CTCF-orchestrated intrachromosomal loop between the IGF2 promoters and the imprinting control region was abrogated in cells with LOI. SUZ12, which docks the PRC2 to IGF2 promoters for H3K27 methylation, was downregulated in LOI cells. These data reveal a new epigenetic control pathway related to the loss of IGF2 imprinting in tumors.