Bidirectional silencing and DNA methylation-sensitive methylation-spreading properties of the Kcnq1 imprinting control region map to the same regions

The mechanisms underlying the phenomenon of genomic imprinting are poorly understood. Accumulating evidence suggests that imprinting control regions (ICR) associated with the imprinted genes play an important role in creation of imprinted expression domains by propagating parent-of-origin-specific epigenetic modifications. We have recently documented that the Kcnq1 ICR unidirectionally blocks enhancer-promoter communications in a methylation-dependent manner in Hep-3B and Jurkat cell lines. In this report we show that the Kcnq1 ICR harbors bidirectional silencing and methylation-sensitive methylation-spreading properties in a lineage-specific manner. We fine map both of these functions to two critical regions, and loss of one these regions results in loss of silencing as well as methylation spreading. The cell type-specific functions of the Kcnq1 ICR suggest binding of cell type-specific factors to various cis elements within the ICR. Fine mapping of the silencing and methylation-spreading functions to the same regions explains the fact that the silencing factors associated with this region primarily repress the neighboring genes and that methylation occurs as a consequence of silencing.