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Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined

Epigenetic marks are fundamental to normal development, but little is known about signals that dictate their placement. Insights have been provided by studies of imprinted loci in mammals, where monoallelic expression is epigenetically controlled. Imprinted expression is regulated by DNA methylation...

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Autores principales: Park, Yoon Jung, Herman, Herry, Gao, Ying, Lindroth, Anders M., Hu, Benjamin Y., Murphy, Patrick J., Putnam, James R., Soloway, Paul D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293921/
https://www.ncbi.nlm.nih.gov/pubmed/22403732
http://dx.doi.org/10.1371/journal.pone.0033024
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author Park, Yoon Jung
Herman, Herry
Gao, Ying
Lindroth, Anders M.
Hu, Benjamin Y.
Murphy, Patrick J.
Putnam, James R.
Soloway, Paul D.
author_facet Park, Yoon Jung
Herman, Herry
Gao, Ying
Lindroth, Anders M.
Hu, Benjamin Y.
Murphy, Patrick J.
Putnam, James R.
Soloway, Paul D.
author_sort Park, Yoon Jung
collection PubMed
description Epigenetic marks are fundamental to normal development, but little is known about signals that dictate their placement. Insights have been provided by studies of imprinted loci in mammals, where monoallelic expression is epigenetically controlled. Imprinted expression is regulated by DNA methylation programmed during gametogenesis in a sex-specific manner and maintained after fertilization. At Rasgrf1 in mouse, paternal-specific DNA methylation on a differential methylation domain (DMD) requires downstream tandem repeats. The DMD and repeats constitute a binary switch regulating paternal-specific expression. Here, we define sequences sufficient for imprinted methylation using two transgenic mouse lines: One carries the entire Rasgrf1 cluster (RC); the second carries only the DMD and repeats (DR) from Rasgrf1. The RC transgene recapitulated all aspects of imprinting seen at the endogenous locus. DR underwent proper DNA methylation establishment in sperm and erasure in oocytes, indicating the DMD and repeats are sufficient to program imprinted DNA methylation in germlines. Both transgenes produce a DMD-spanning pit-RNA, previously shown to be necessary for imprinted DNA methylation at the endogenous locus. We show that when pit-RNA expression is controlled by the repeats, it regulates DNA methylation in cis only and not in trans. Interestingly, pedigree history dictated whether established DR methylation patterns were maintained after fertilization. When DR was paternally transmitted followed by maternal transmission, the unmethylated state that was properly established in the female germlines could not be maintained. This provides a model for transgenerational epigenetic inheritance in mice.
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spelling pubmed-32939212012-03-08 Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined Park, Yoon Jung Herman, Herry Gao, Ying Lindroth, Anders M. Hu, Benjamin Y. Murphy, Patrick J. Putnam, James R. Soloway, Paul D. PLoS One Research Article Epigenetic marks are fundamental to normal development, but little is known about signals that dictate their placement. Insights have been provided by studies of imprinted loci in mammals, where monoallelic expression is epigenetically controlled. Imprinted expression is regulated by DNA methylation programmed during gametogenesis in a sex-specific manner and maintained after fertilization. At Rasgrf1 in mouse, paternal-specific DNA methylation on a differential methylation domain (DMD) requires downstream tandem repeats. The DMD and repeats constitute a binary switch regulating paternal-specific expression. Here, we define sequences sufficient for imprinted methylation using two transgenic mouse lines: One carries the entire Rasgrf1 cluster (RC); the second carries only the DMD and repeats (DR) from Rasgrf1. The RC transgene recapitulated all aspects of imprinting seen at the endogenous locus. DR underwent proper DNA methylation establishment in sperm and erasure in oocytes, indicating the DMD and repeats are sufficient to program imprinted DNA methylation in germlines. Both transgenes produce a DMD-spanning pit-RNA, previously shown to be necessary for imprinted DNA methylation at the endogenous locus. We show that when pit-RNA expression is controlled by the repeats, it regulates DNA methylation in cis only and not in trans. Interestingly, pedigree history dictated whether established DR methylation patterns were maintained after fertilization. When DR was paternally transmitted followed by maternal transmission, the unmethylated state that was properly established in the female germlines could not be maintained. This provides a model for transgenerational epigenetic inheritance in mice. Public Library of Science 2012-03-05 /pmc/articles/PMC3293921/ /pubmed/22403732 http://dx.doi.org/10.1371/journal.pone.0033024 Text en Park et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Park, Yoon Jung
Herman, Herry
Gao, Ying
Lindroth, Anders M.
Hu, Benjamin Y.
Murphy, Patrick J.
Putnam, James R.
Soloway, Paul D.
Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined
title Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined
title_full Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined
title_fullStr Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined
title_full_unstemmed Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined
title_short Sequences Sufficient for Programming Imprinted Germline DNA Methylation Defined
title_sort sequences sufficient for programming imprinted germline dna methylation defined
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293921/
https://www.ncbi.nlm.nih.gov/pubmed/22403732
http://dx.doi.org/10.1371/journal.pone.0033024
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