In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions

By Simon P. Quenneville, G. Verde, A. Corsinotti, A. Kapopoulou, Johan Jakobsson, Sandra Offner, I. Baglivo, P. V. Pedone, G. Grimaldi, A. Riccio and 1 more. 2011

590 citations recorded by the source corpus.

Summary The maintenance of H3K9 and DNA methylation at imprinting control regions (ICRs) during early embryogenesis is key to the regulation of imprinted genes. Here, we reveal that ZFP57, its cofactor KAP1, and associated effectors bind selectively to the H3K9me3-bearing, DNA-methylated allele of ICRs in ES cells. KAP1 deletion induces a loss of heterochromatin marks at ICRs, whereas deleting ZFP57 or DNMTs leads to ICR DNA demethylation. Accordingly, we find that ZFP57 and KAP1 associated with DNMTs and hemimethylated DNA-binding NP95. Finally, we identify the methylated TGCCGC hexanucleotide as the motif that is recognized by ZFP57 in all ICRs and in several tens of additional loci, several of which are at least ZFP57-dependently methylated in ES cells. These results significantly advance our understanding of imprinting and suggest a general mechanism for the protection of specific loci against the wave of DNA demethylation that affects the mammalian genome during early embryogenesis.

Subfields: Genetics, Molecular Biology, Pediatrics, Perinatology and Child Health

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Wolf Reik
2. W. Dean
3. Jörn Walter
4. Guo-li Ming
5. Hongjun Song
6. Fátima Santos
7. Dirk Schübeler
8. Oliver Stegle

In Molecular Biology

1. Wolf Reik
2. W. Dean
3. Jörn Walter
4. Hongjun Song
5. Guo-li Ming
6. Felix Krueger
7. Fátima Santos
8. Simon R. Andrews

In Pediatrics, Perinatology and Child Health

1. Wolf Reik
2. Jörn Walter
3. W. Dean
4. Fátima Santos
5. Oliver Stegle
6. Jussi Taipale
7. E. Li

Citations in the corpus

• Impact of cytosine methylation on DNA binding specificities of human transcription factors (2017, positive): “In contrast to most previously reported cases [for example, (9, 10, 12, 17, 18)], we found that methylation can affect TF binding positively in many cases [see also (16, 62)].”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, unknown): “Recent evidence suggests that maintenance of 5mC at ICRs is perhaps conferred through targeting DNMT1 and/or DNMT3A to these regions by zinc finger transcription factor ZFP57 and its partner, KAP1 (also known as TRIM28) (Li et al., 2008; Messerschmidt et al., 2012; Quenneville et al., 2011).”
• Structural basis for Klf4 recognition of methylated DNA (2014, methodology): “Zfp57 recognizes the sequence GMGGCA [where M=5mC; in the literature, the sequence of the opposite strand TGCCGC was initially used (43)].”
• A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development (2015, background): “ZFP57 (or also called ZNF698) is a notable KRAB-ZFP protein known to establish/maintain methylation of ICRs through recognition of consensus methylated DNA sequence (Quenneville et al., 2011).”
• DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, background): “Loss of ZFP57 in mouse embryos and ESCs causes hypomethylation of both paternal and maternal ICRs and misregulation of imprinted genes (Li et al. 2008; Quenneville et al. 2011; Zuo et al. 2012).”
• DeepCpG: accurate prediction of single-cell DNA methylation states using deep learning (2016, background): “These include Foxa2 [49, 50] and Srf [51, 52], which are implicated in cell differentiation and embryonic development, as well as Zfp637 [53, 54], a zinc finger protein that has recently been linked to spermatogenesis in mouse.”
• Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence (2014, unknown): “Zfp57 (with two ZnFs in tandem) and Klf4 (with three) recognize the triplet 5 9 -G-5mC-G-3 9 within a 6-base-pair (bp) (Quenneville et al. 2011) and a 9-bp (Chen et al. 2008) sequence, respectively.”
• The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells (2012, background): “(D) Percentage of promoters that overlap or are nearby (<1kb distance) to confirmed Zfp57-binding sites (Quenneville et al., 2011).”
• DNA methylation presents distinct binding sites for human transcription factors (2013, background): “In this study we have identified numerous human TFs across various subfamilies that showed mCpG- and sequence-dependent binding activity, a much more prevalent phenomenon than previously appreciated (Karlsson et al., 2008; Rishi et al., 2010; Quenneville et al., 2011; Liu et al., 2012).”
• Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, unknown): “…at Distal Regulatory Elements 5mC is thought to confer specificity to gene regulation by influencing transcription factor binding or serving as a substrate of recognition for chromatin regulators (Bird, 2011; Chen and Riggs, 2011; Jaenisch and Bird, 2003; Quenneville et al., 2011).”