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Genome Biol. 2015 May 30;16:112. doi: 10.1186/s13059-015-0672-7.

Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression.

Author information

1
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. ruslan.strogantsev@babraham.ac.uk.
2
Present address: Epigenetics ISP, Babraham Institute, Cambridge, CB22 3AT, UK. ruslan.strogantsev@babraham.ac.uk.
3
Bioinformatics Department, Babraham Institute, Cambridge, CB22 3AT, UK. felix.krueger@babraham.ac.uk.
4
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. kyamazawa@keio.jp.
5
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. hs523@cam.ac.uk.
6
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. pg362@cam.ac.uk.
7
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. mg626@cam.ac.uk.
8
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. kirsten.mcewen@imperial.ac.uk.
9
The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK. bwsun@sibs.ac.cn.
10
The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK. ralp2@cam.ac.uk.
11
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. afsmith@mole.bio.cam.ac.uk.
12
Present address: Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK. afsmith@mole.bio.cam.ac.uk.

Abstract

BACKGROUND:

Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence.

RESULTS:

Here, we comprehensively map sequence-specific ZFP57 binding sites in an allele-specific manner using hybrid ES cell lines from reciprocal crosses between C57BL/6J and Cast/EiJ mice, assigning allele specificity to approximately two-thirds of all binding sites. While half of these are biallelic and include endogenous retrovirus (ERV) targets, the rest show monoallelic binding based either on parental origin or on genetic background of the allele. Parental-origin allele-specific binding is methylation-dependent and maps only to imprinting control differentially methylated regions (DMRs) established in the germline. We identify a novel imprinted gene, Fkbp6, which has a critical function in mouse male germ cell development. Genetic background-specific sequence differences also influence ZFP57 binding, as genetic variation that disrupts the consensus binding motif and its methylation is often associated with monoallelic expression of neighboring genes.

CONCLUSIONS:

The work described here uncovers further roles for ZFP57-mediated regulation of genomic imprinting and identifies a novel mechanism for genetically determined monoallelic gene expression.

PMID:
26025256
PMCID:
PMC4491874
DOI:
10.1186/s13059-015-0672-7
[Indexed for MEDLINE]
Free PMC Article

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