ZFP57 maintains the parent-of-origin-specific expression of the imprinted genes and differentially affects non-imprinted targets in mouse embryonic stem cells

• Published in: Nucleic acids research Vol. 44; no. 17; pp. 8165 - 8178
• Main Authors: Riso, Vincenzo, Cammisa, Marco, Kukreja, Harpreet, Anvar, Zahra, Verde, Gaetano, Sparago, Angela, Acurzio, Basilia, Lad, Shraddha, Lonardo, Enza, Sankar, Aditya, Helin, Kristian, Feil, Robert, Fico, Annalisa, Angelini, Claudia, Grimaldi, Giovanna, Riccio, Andrea
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 30.09.2016
• Subjects: Animals; Binding Sites - genetics; Biochemistry, Molecular Biology; Cell Differentiation - genetics; CpG Islands - genetics; Development Biology; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Gene regulation, Chromatin and Epigenetics; Genetic Loci; Genetics; Genomic Imprinting; Histones - metabolism; Life Sciences; Lysine - metabolism; Methylation; Mice; Models, Genetic; Mouse Embryonic Stem Cells - metabolism; Nuclear Proteins - metabolism; Repressor Proteins - metabolism
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkw505

ZFP57 is necessary for maintaining repressive epigenetic modifications at Imprinting control regions (ICRs). In mouse embryonic stem cells (ESCs), ZFP57 binds ICRs (ICRBS) and many other loci (non-ICRBS). To address the role of ZFP57 on all its target sites, we performed high-throughput and multi-locus analyses of inbred and hybrid mouse ESC lines carrying different gene knockouts. By using an allele-specific RNA-seq approach, we demonstrate that ZFP57 loss results in derepression of the imprinted allele of multiple genes in the imprinted clusters. We also find marked epigenetic differences between ICRBS and non-ICRBS suggesting that different cis-acting regulatory functions are repressed by ZFP57 at these two classes of target loci. Overall, these data demonstrate that ZFP57 is pivotal to maintain the allele-specific epigenetic modifications of ICRs that in turn are necessary for maintaining the imprinted expression over long distances. At non-ICRBS, ZFP57 inactivation results in acquisition of epigenetic features that are characteristic of poised enhancers, suggesting that another function of ZFP57 in early embryogenesis is to repress cis-acting regulatory elements whose activity is not yet required.