The role of ZFP57 and additional KRAB-zinc finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances
Monteagudo-Sánchez, Ana (Institut d'Investigació Biomèdica de Bellvitge)
Hernandez Mora, J. R. (Institut d'Investigació Biomèdica de Bellvitge)
Simon, C. (Department of Obstetrics and Gynecology. BIDMC. Harvard University)
Burton, A. (Institute of Epigenetics and Stem Cells. Helmholtz Zentrum München)
Tenorio, Jair (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Lapunzina, Pablo (ITHACA. European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability)
Clark, S. (Epigenetics Programme. The Babraham Institute)
Esteller, M. (Centro de Investigación Biomédica en Red de Cáncer)
Kelsey, G. (University of Cambridge. Centre for Trophoblast Research)
López-Siguero, J. P. (Hospital Regional Universitario de Málaga)
De Nanclares, G. P. (Instituto de Investigación Sanitaria Bioaraba (Vitoria, País Basc))
Torres-Padilla, M. E. (Institute of Epigenetics and Stem Cells. Helmholtz Zentrum München)
Monk, D. (University of East Anglia. Biomedical Research Centre)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad BFU2014-53093-R Ministerio de Economía y Competitividad BFU2017-85571-R Instituto de Salud Carlos III PI16-00073 Instituto de Salud Carlos III PI15-01481 Ministerio de Economía y Competitividad BES-2015-072547
Nota:	Altres ajuts: Department of Health of the Basque Government [GV2017/111040].
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Beckwith-Wiedemann Syndrome ; Cohort Studies ; DNA (Cytosine-5-)-Methyltransferases ; DNA Methylation ; Embryo, Mammalian ; Genomic Imprinting ; Germ Cells ; Humans ; Microarray Analysis ; Mutation ; Oocytes ; Pedigree ; Pseudohypoparathyroidism ; Repressor Proteins ; RNA-Seq ; Siblings ; Transcriptome ; Tripartite Motif-Containing Protein 28
Publicat a:	Nucleic acids research, Vol. 48 Núm. 20 (18 2020) , p. 11394-11407, ISSN 1362-4962

DOI: 10.1093/nar/gkaa837
PMID: 33053156

14 p, 5.6 MB

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