The role of ZFP57 and additional KRAB-zinc finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances.
Beckwith-Wiedemann Syndrome
/ metabolism
Cohort Studies
DNA (Cytosine-5-)-Methyltransferases
/ metabolism
DNA Methylation
DNA Methyltransferase 3A
Embryo, Mammalian
/ metabolism
Genomic Imprinting
Germ Cells
/ metabolism
Humans
Microarray Analysis
Mutation
Oocytes
/ metabolism
Pedigree
Pseudohypoparathyroidism
/ metabolism
RNA-Seq
Repressor Proteins
/ genetics
Siblings
Transcriptome
Tripartite Motif-Containing Protein 28
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
18 11 2020
18 11 2020
Historique:
accepted:
13
10
2020
revised:
10
09
2020
received:
09
06
2020
pubmed:
15
10
2020
medline:
29
12
2020
entrez:
14
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33053156
pii: 5923428
doi: 10.1093/nar/gkaa837
pmc: PMC7672439
doi:
Substances chimiques
DNMT3A protein, human
0
Repressor Proteins
0
ZFP57 protein, human
0
ZNF202 protein, human
0
DNA (Cytosine-5-)-Methyltransferases
EC 2.1.1.37
DNA Methyltransferase 3A
EC 2.1.1.37
TRIM28 protein, human
EC 2.3.2.27
Tripartite Motif-Containing Protein 28
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11394-11407Subventions
Organisme : Medical Research Council
ID : MR/K011332/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S000437/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BBS/E/B/000C0423
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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