Establishment of paternal methylation imprint at the <i>H19/Igf2</i> imprinting control region.

Abstract

The insulator model explains the workings of the <i>H19</i> and <i>Igf2</i> imprinted domain in the soma, where insulation of the <i>Igf2</i> promoter from its enhancers occurs by CTCF in the maternally inherited unmethylated chromosome but not the paternally inherited methylated allele. The molecular mechanism that targets paternal methylation imprint establishment to the imprinting control region (ICR) in the male germline is unknown. We tested the function of prospermatogonia-specific broad low-level transcription in this process using mouse genetics. Paternal imprint establishment was abnormal when transcription was stopped at the entry point to the ICR. The germline epimutation persisted into the paternal allele of the soma, resulting in reduced <i>Igf2</i> in fetal organs and reduced fetal growth, consistent with the insulator model and insulin-like growth factor 2 (IGF2)'s role as fetal growth factor. These results collectively support the role of broad low-level transcription through the <i>H19/Igf2</i> ICR in the establishment of its paternal methylation imprint in the male germ line, with implications for Silver-Russell syndrome.