title: Zinc finger protein ZFP57 requires its co-factor to recruit DNA methyltransferases and maintains DNA methylation imprint in embryonic stem cells via its transcriptional repression domain.
abstract: Previously, we discovered that ZFP57 is a maternal-zygotic effect gene, and it maintains DNA methylation genomic imprint at multiple imprinted regions in mouse embryos. Despite these findings, it remains elusive how DNA methyltransferases are targeted to the imprinting control regions to initiate and maintain DNA methylation imprint. To gain insights into these essential processes in genomic imprinting, we examined how ZFP57 maintains genomic DNA methylation imprint in mouse embryonic stem (ES) cells. Here we demonstrate that the loss of ZFP57 in mouse ES cells led to a complete loss of genomic DNA methylation imprint at multiple imprinted regions, similar to its role in mouse embryos. However, reintroduction of ZFP57 into Zfp57-null ES cells did not result in reacquisition of DNA methylation imprint, suggesting that the memory for genomic imprinting had been lost or altered in Zfp57-null ES cells in culture. Interestingly, ZFP57 and DNA methyltransferases could form complexes in the presence of KAP1/TRIM28/TIF1β when co-expressed in COS cells. We also found that the wild-type exogenous ZFP57 but not the mutant ZFP57 lacking the KRAB box that interacts with its co-factor KAP1/TRIM28/TIF1β could substitute for the endogenous ZFP57 in maintaining the DNA methylation imprint in ES cells. These results suggest that ZFP57 may recruit DNA methyltransferases to its target regions to maintain DNA methylation imprint, and this interaction is likely facilitated by KAP1/TRIM28/TIF1β.
authors.affiliation: Black Family Stem Cell Institute, Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Zuo
authors.forename: Jipo
authors.initials: J
authors.lastname: Sheng
authors.forename: Ho-Tak
authors.initials: HT
authors.lastname: Lau
authors.forename: Carol M
authors.initials: CM
authors.lastname: McDonald
authors.forename: Monica
authors.initials: M
authors.lastname: Andrade
authors.forename: Dana E
authors.initials: DE
authors.lastname: Cullen
authors.forename: Fong T
authors.initials: FT
authors.lastname: Bell
authors.forename: Michelina
authors.initials: M
authors.lastname: Iacovino
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xu
authors.forename: Xiajun
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019175:DNA Methylation / Q000502:physiology*; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018392:Genomic Imprinting / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D016335:Zinc Fingers
chemical_list: D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D012097:Repressor Proteins; C501529:Zfp-57 protein, mouse; D015254:DNA Modification Methylases; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28