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

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.

Humanization of a tandem repeat in IG-DMR causes stochastic restoration of paternal imprinting at mouseDlk1-Dio3domain

“…Our results showed that ZFP57 binds very weakly, if at all, to hRep in IG-DMR +/hRep embryos. It is not clear whether the presence of endogenous ZFP445 is involved in unstable hRep methylation, but ZFP445, or other KRAB-ZNFs such as ZNF202, is a candidate for an as-yet-unknown factor functioning in place of ZFP57 ( 26 ). Further studies are required to understand the molecular mechanisms involving KRAB-ZFP and TRIM28 in the maintenance of methylation imprints at hRep.…”

DNA Methylation Dynamics in the Female Germline and Maternal-Effect Mutations That Disrupt Genomic Imprinting

“…In a recent study, for the first time a homozygous ZFP445 variant was found. This pathogenic variant caused Temple syndrome and MLID in the patient [65,67,68].…”

“…In mice, ZFP57 is continually expressed from the oocyte to the early embryo, and it has been shown that oocyte expression of ZFP57 is required for the proper maintenance of gDMRs [63]. In humans, ZFP57 is expressed only in the early embryo with zygotic genome activation [45,65]. It is unclear if this difference in expression has any effect on function, but loss of function mutations of human ZFP57 disrupt the maintenance of imprinting resulting in MLID [66].…”

Alteration of Genomic Imprinting after Assisted Reproductive Technologies and Long-Term Health

“…ZFP57 recruits TRIM28 and KAP1 complexes, which promote the recruitment of SETDB1 and DNMT1 to maintain the methylation at those ICRs [ 93 ]. Recessive mutations in ZFP57 have been identified in transient neonatal diabetes cases, a congenital imprinting disorder, with a specific pattern of MLIDs [ 94 , 95 ].…”