Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Yonatan Stelzer; Hao Wu; Yuelin Song; Chikdu S. Shivalila; Styliani Markoulaki; Rudolf Jaenisch

doi:10.1016/j.celrep.2016.08.066

Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Yonatan Stelzer, Hao Wu, Yuelin Song, Chikdu S. Shivalila, Styliani Markoulaki, Rudolf Jaenisch^*

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Parent-specific differentially methylated regions (DMRs) are established during gametogenesis and regulate parent-specific expression of imprinted genes. Monoallelic expression of imprinted genes is essential for development, suggesting that imprints are faithfully maintained in embryos and adults. To test this hypothesis, we targeted a reporter for genomic methylation to the imprinted Dlk1-Dio3 intergenic DMR (IG-DMR) to assess the methylation of both parental alleles at single-cell resolution. Biallelic gain or loss of IG-DMR methylation occurred in a small fraction of mouse embryonic stem cells, significantly affecting developmental potency. Mice carrying the reporter in either parental allele showed striking parent-specific changes in IG-DMR methylation, causing substantial and consistent tissue- and cell-type-dependent signatures in embryos and postnatal animals. Furthermore, dynamics in DNA methylation persisted during adult neurogenesis, resulting in inter-individual diversity. This substantial cell-cell DNA methylation heterogeneity implies that dynamic DNA methylation variations in the adult may be of functional importance.

Original language	English (US)
Pages (from-to)	3167-3180
Number of pages	14
Journal	Cell reports
Volume	16
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2016.08.066
State	Published - Sep 20 2016

Funding

We thank Patti Wisniewski and Colin Zollo for FACS analyses and cell sorting, Wendy Salmon for assistance with confocal imaging, and Maria Mihaylova for liver cell dissociation. The authors would like to thank Frank Soldner, Malkiel Cohen, Robert N. Plasschaert, and Shawn Liu for critically reading the manuscript. This study was supported by NIH grant HD 045022. Y. Stelzer is supported by a Human Frontier Postdoctoral Fellowship. H.W. is supported by a NARSAD Young Investigator Fellowship (grant 22950). R.J. is an advisor to Stemgent and a cofounder of Fate Therapeutics and Fulcrum Therapeutics.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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abstract = "Parent-specific differentially methylated regions (DMRs) are established during gametogenesis and regulate parent-specific expression of imprinted genes. Monoallelic expression of imprinted genes is essential for development, suggesting that imprints are faithfully maintained in embryos and adults. To test this hypothesis, we targeted a reporter for genomic methylation to the imprinted Dlk1-Dio3 intergenic DMR (IG-DMR) to assess the methylation of both parental alleles at single-cell resolution. Biallelic gain or loss of IG-DMR methylation occurred in a small fraction of mouse embryonic stem cells, significantly affecting developmental potency. Mice carrying the reporter in either parental allele showed striking parent-specific changes in IG-DMR methylation, causing substantial and consistent tissue- and cell-type-dependent signatures in embryos and postnatal animals. Furthermore, dynamics in DNA methylation persisted during adult neurogenesis, resulting in inter-individual diversity. This substantial cell-cell DNA methylation heterogeneity implies that dynamic DNA methylation variations in the adult may be of functional importance.",

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note = "Funding Information: We thank Patti Wisniewski and Colin Zollo for FACS analyses and cell sorting, Wendy Salmon for assistance with confocal imaging, and Maria Mihaylova for liver cell dissociation. The authors would like to thank Frank Soldner, Malkiel Cohen, Robert N. Plasschaert, and Shawn Liu for critically reading the manuscript. This study was supported by NIH grant HD 045022. Y. Stelzer is supported by a Human Frontier Postdoctoral Fellowship. H.W. is supported by a NARSAD Young Investigator Fellowship (grant 22950). R.J. is an advisor to Stemgent and a cofounder of Fate Therapeutics and Fulcrum Therapeutics. Publisher Copyright: {\textcopyright} 2016 The Authors",

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Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Abstract

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