The role of ZFP57 and additional KRAB-Zinc Finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances

Ana Monteagudo Sanchez, Jose Ramon Hernandez Mora, Carlos Simon, Adam Burton, Jair Tenorio, Pablo Lapunzina, Stephen Clark, Manel Esteller, Gavin Kelsey, Juan Pedro López-Siguer, Guiomar Perez de Nanclares, Maria-Elena Torres-Padilla, David Monk

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Abstract

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.
Original languageEnglish
Pages (from-to)11394–11407
Number of pages14
JournalNucleic Acids Research
Volume48
Issue number20
Early online date14 Oct 2020
DOIs
Publication statusPublished - 18 Nov 2020

Keywords

  • Imprinting
  • ZFP57

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