Establishment of paternal methylation imprint at the H19/Igf2 imprinting control region

Author:

Liao Ji1ORCID,Song Sangmin2,Gusscott Samuel3ORCID,Fu Zhen4ORCID,VanderKolk Ivan1ORCID,Busscher Brianna M.1ORCID,Lau Kin H.4ORCID,Brind’Amour Julie3,Szabó Piroska E.1ORCID

Affiliation:

1. Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.

2. Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA.

3. Département de Biomédecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec J2S, Canada.

4. Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI 49503, USA.

Abstract

The insulator model explains the workings of the H19 and Igf2 imprinted domain in the soma, where insulation of the Igf2 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 Igf2 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 H19/Igf2 ICR in the establishment of its paternal methylation imprint in the male germ line, with implications for Silver-Russell syndrome.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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