title: Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression.
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.
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. ruslan.strogantsev@babraham.ac.uk.|Present address: Epigenetics ISP, Babraham Institute, Cambridge, CB22 3AT, UK. ruslan.strogantsev@babraham.ac.uk.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Strogantsev
authors.affiliation: Bioinformatics Department, Babraham Institute, Cambridge, CB22 3AT, UK. felix.krueger@babraham.ac.uk.
authors.forename: Felix
authors.initials: F
authors.lastname: Krueger
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. kyamazawa@keio.jp.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yamazawa
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. hs523@cam.ac.uk.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. pg362@cam.ac.uk.
authors.forename: Poppy
authors.initials: P
authors.lastname: Gould
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. mg626@cam.ac.uk.
authors.forename: Megan
authors.initials: M
authors.lastname: Goldman-Roberts
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. kirsten.mcewen@imperial.ac.uk.
authors.forename: Kirsten
authors.initials: K
authors.lastname: McEwen
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK. bwsun@sibs.ac.cn.
authors.forename: Bowen
authors.initials: B
authors.lastname: Sun
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK. ralp2@cam.ac.uk.
authors.forename: Roger
authors.initials: R
authors.lastname: Pedersen
authors.affiliation: Department of Physiology Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EG, UK. afsmith@mole.bio.cam.ac.uk.|Present address: Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK. afsmith@mole.bio.cam.ac.uk.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D014644:Genetic Variation; D018392:Genomic Imprinting; D042421:Histone Code; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; C501529:Zfp-57 protein, mouse