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Monteagudo-Sánchez, A.* ; Hernandez Mora, J.R.* ; Simon, C.* ; Burton, A. ; Tenorio, J.* ; Lapunzina, P.* ; Clark, S.* ; Esteller, M.* ; Kelsey, G.* ; López-Siguero, J.P.* ; de Nanclares, G.P.* ; Torres-Padilla, M.E. ; Monk, D.*

The role of ZFP57 and additional KRAB-zinc finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances.

Nucleic Acids Res. 48, 11394-11407 (2020)
Postprint Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation that is resistant to embryonic reprogramming, resulting in parental origin-specific monoallelic gene expression. A subset of individuals affected by imprinting disorders (IDs) displays multi-locus imprinting disturbances (MLID), which may result from aberrant establishment of imprinted differentially methylated regions (DMRs) in gametes or their maintenance in early embryogenesis. Here we investigated the extent of MLID in a family harbouring a ZFP57 truncating variant and characterize the interactions between human ZFP57 and the KAP1 co-repressor complex. By ectopically targeting ZFP57 to reprogrammed loci in mouse embryos using a dCas9 approach, we confirm that ZFP57 recruitment is sufficient to protect oocyte-derived methylation from reprogramming. Expression profiling in human pre-implantation embryos and oocytes reveals that unlike in mice, ZFP57 is only expressed following embryonic-genome activation, implying that other KRAB-zinc finger proteins (KZNFs) recruit KAP1 prior to blastocyst formation. Furthermore, we uncover ZNF202 and ZNF445 as additional KZNFs likely to recruit KAP1 to imprinted loci during reprogramming in the absence of ZFP57. Together, these data confirm the perplexing link between KZFPs and imprint maintenance and highlight the differences between mouse and humans in this respect.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dna Methylation; Analysis Reveals; Gene; Hypomethylation; Mechanisms; Mutations; Chromatin; Isoforms; Loci
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Zeitschrift Nucleic Acids Research
Quellenangaben Band: 48, Heft: 20, Seiten: 11394-11407 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epigenetics and Stem Cells (IES)
POF Topic(s) 30204 - Cell Programming and Repair
Forschungsfeld(er) Stem Cell and Neuroscience
PSP-Element(e) G-506200-001
Förderungen Internal UEA funding
European Union Regional Development Fund (FEDER)
Instituto de Salud Carlos III (Institute of Health Carlos III) of the Spanish Ministry of Economy and Competitiveness
European Regional Development Fund
Department of Health of the Basque Government
National Agency of Research (ISCIII-FEDER)
UK Medical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
FPI PhD studentship from MINECO
EMBO short-term fellowship
Spanish Ministry of Economy and Competitiveness (MINECO)
DOI 10.1093/nar/gkaa837
WOS ID WOS:000606018600019
Scopus ID 85096357051
Erfassungsdatum 2020-12-01
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