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

Aberrant imprinting of the insulin-like growth factor II (IGF2) gene is a molecular hallmark of many tumors. Reactivationof thenormallysuppressedmaternal allele leads toupregulationof thegrowth factor thatpromotes 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,we found that incells characterizedbymaintenanceof IGF2 imprinting, three IGF2promo-tersweredifferentiallymodified,with thesuppressedallele heavilymethylated athistoneH3K27while the active allelewasunmethylated. In theLOI tumors,however,bothalleleswereunmethylated,andcorrespondingly there wasnobindingofSUZ12, thedocking factorof thepolycombrepressivecomplex2 (PRC2), andof thezincfinger-containing transcription factor (CTCF) that recruits thePRC2. Using chromatin conformation capture, we found that the CTCF-orchestrated intrachromosomal loop between the IGF2 promoters and the imprinting control regionwas abrogated in cellswith LOI. SUZ12,which docks thePRC2 to IGF2promoters for H3K27methylation, was downregulated in LOI cells. These data reveal a new epigenetic control pathway related to the loss of IGF2 imprinting in tumors