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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.<\/jats:p>","DOI":"10.1093\/nar\/gkaa837","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T19:30:44Z","timestamp":1602617444000},"page":"11394-11407","source":"Crossref","is-referenced-by-count":60,"title":["The role of ZFP57 and additional KRAB-zinc finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances"],"prefix":"10.1093","volume":"48","author":[{"given":"Ana","family":"Monteagudo-S\u00e1nchez","sequence":"first","affiliation":[{"name":"Imprinting and Cancer group, Bellvitge Institute for Biomedical Research, Gran via, L\u2019Hospitalet de Llobregat, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Ramon","family":"Hernandez\u00a0Mora","sequence":"additional","affiliation":[{"name":"Imprinting and Cancer group, Bellvitge Institute for Biomedical Research, Gran via, L\u2019Hospitalet de Llobregat, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Valencia University and INCLIVA, Valencia, Spain"},{"name":"Department of Obstetrics and Gynecology, BIDMC, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Burton","sequence":"additional","affiliation":[{"name":"Institute of Epigenetics and Stem Cells, Helmholtz Zentrum M\u00fcnchen, M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jair","family":"Tenorio","sequence":"additional","affiliation":[{"name":"Medical and Molecular Genetics Institute, University Hospital La Paz, Madrid, Spain"},{"name":"CIBERER, Centro de Investigacion Biomedica en Red de Enfermedades Raras, ISCIII, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[{"name":"Medical and Molecular Genetics Institute, University Hospital La Paz, Madrid, Spain"},{"name":"CIBERER, Centro de Investigacion Biomedica en Red de Enfermedades Raras, ISCIII, Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Clark","sequence":"additional","affiliation":[{"name":"Epigenetics Programme, The Babraham Institute, Babraham, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manel","family":"Esteller","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukeamia Research Institute, Can Ruti, Cami de les Escoles, Badalona, Barcelona, Spain"},{"name":"Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain"},{"name":"Institucio Catalana de Recerca i Estudis Avan\u00e7ats (ICREA), Barcelona, Catalonia, Spain"},{"name":"Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9762-5634","authenticated-orcid":false,"given":"Gavin","family":"Kelsey","sequence":"additional","affiliation":[{"name":"Epigenetics Programme, The Babraham Institute, Babraham, Cambridge, UK"},{"name":"Centre for Trophoblast Research, University of Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pedro","family":"L\u00f3pez-Siguero","sequence":"additional","affiliation":[{"name":"Servicio de Endocrinolog\u00eda Pedi\u00e1trica, Hospital Carlos de Haya, M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiomar Perez","family":"de\u00a0Nanclares","sequence":"additional","affiliation":[{"name":"(Epi)Genetics Laboratory, BioAraba Research Health Institute, Araba University Hospital, Vitoria-Gasteiz, Alava, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Elena","family":"Torres-Padilla","sequence":"additional","affiliation":[{"name":"Institute of Epigenetics and Stem Cells, Helmholtz Zentrum M\u00fcnchen, M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8991-0497","authenticated-orcid":false,"given":"David","family":"Monk","sequence":"additional","affiliation":[{"name":"Imprinting and Cancer group, Bellvitge Institute for Biomedical Research, Gran via, L\u2019Hospitalet de Llobregat, Barcelona, Spain"},{"name":"Biomedical Research Centre, University of East Anglia, Norwich Research Park, Norwich, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,10,14]]},"reference":[{"key":"2020111803364655500_B1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.biocel.2015.04.014","article-title":"Germline-derived DNA methylation and early embryo epigenetic reprogramming: the selected survival of imprints","volume":"67","author":"Monk","year":"2015","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2020111803364655500_B2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41576-018-0092-0","article-title":"Genomic imprinting disorders: lessons on how genome, epigenome and environment interact","volume":"20","author":"Monk","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"2020111803364655500_B3","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrg3032","article-title":"Genomic imprinting: the emergence of an epigenetic paradigm","volume":"12","author":"Ferguson-Smith","year":"2011","journal-title":"Nat Rev Genet."},{"key":"2020111803364655500_B4","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1101\/gr.196139.115","article-title":"Pervasive polymorphic imprinted methylation in the human placenta","volume":"26","author":"Hanna","year":"2016","journal-title":"Genome Res."},{"key":"2020111803364655500_B5","doi-asserted-by":"crossref","first-page":"S152","DOI":"10.1016\/j.ajog.2015.06.032","article-title":"Genomic imprinting in the human placenta","volume":"213","author":"Monk","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"2020111803364655500_B6","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.diff.2011.01.007","article-title":"Developmental regulation of somatic imprints","volume":"81","author":"John","year":"2011","journal-title":"Differentiation"},{"key":"2020111803364655500_B7","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.biocel.2015.04.004","article-title":"Chromatin mechanisms in the developmental control of imprinted gene expression","volume":"67","author":"Sanli","year":"2015","journal-title":"Int. J. Biochem. 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Genet."},{"key":"2020111803364655500_B21","doi-asserted-by":"crossref","first-page":"505","DOI":"10.2337\/dc12-0700","article-title":"Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up","volume":"36","author":"Boonen","year":"2013","journal-title":"Diabetes Care."},{"key":"2020111803364655500_B22","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s00592-018-1239-3","article-title":"Transient neonatal diabetes mellitus and hypomethylation at additional imprinted loci: novel ZFP57 mutation and review on the literature","volume":"56","author":"Touati","year":"2019","journal-title":"Acta Diabetol."},{"key":"2020111803364655500_B23","first-page":"595","article-title":"Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes","volume":"34","author":"Court","year":"2013","journal-title":"Hum. Mutat."},{"key":"2020111803364655500_B24","first-page":"026","article-title":"Epigenetic symmetry of DLGAP2: pre-implantation maternal methylation switches to a random monoallelic profile in somatic tissues","volume":"2","author":"S\u00e1nchez","year":"2018","journal-title":"OBM Genetics"},{"key":"2020111803364655500_B25","doi-asserted-by":"crossref","first-page":"941","DOI":"10.2217\/epi-2017-0172","article-title":"Characterization of parent-of-origin methylation using the Illumina Infinium MethylationEPIC array platform","volume":"10","author":"Hernandez\u00a0Mora","year":"2018","journal-title":"Epigenomics"},{"key":"2020111803364655500_B26","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1101\/gr.164913.113","article-title":"Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment","volume":"24","author":"Court","year":"2014","journal-title":"Genome Res."},{"key":"2020111803364655500_B27","doi-asserted-by":"crossref","first-page":"e1006427","DOI":"10.1371\/journal.pgen.1006427","article-title":"Human Oocyte-Derived methylation differences persist in the placenta revealing widespread transient imprinting","volume":"12","author":"Sanchez-Delgado","year":"2016","journal-title":"PLos Genet."},{"key":"2020111803364655500_B28","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nprot.2015.041","article-title":"Multiplexed locus-specific analysis of DNA methylation in single cells","volume":"10","author":"Cheow","year":"2015","journal-title":"Nat. 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