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

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          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.

          Highlights

          ► ZFP57/KAP1 bind all methylated imprinted control regions in ES cells ► ZFP57/KAP1 bind other nonimprinted methylated sequences in ES cells ► ZFP57/KAP1 are necessary for DNA and histone methylation maintenance ► ZFP57 recognizes a methylated hexanucleotide with two C2H2 zinc fingers

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          Stability and flexibility of epigenetic gene regulation in mammalian development.

          Wolf Reik (2007)
          During development, cells start in a pluripotent state, from which they can differentiate into many cell types, and progressively develop a narrower potential. Their gene-expression programmes become more defined, restricted and, potentially, 'locked in'. Pluripotent stem cells express genes that encode a set of core transcription factors, while genes that are required later in development are repressed by histone marks, which confer short-term, and therefore flexible, epigenetic silencing. By contrast, the methylation of DNA confers long-term epigenetic silencing of particular sequences--transposons, imprinted genes and pluripotency-associated genes--in somatic cells. Long-term silencing can be reprogrammed by demethylation of DNA, and this process might involve DNA repair. It is not known whether any of the epigenetic marks has a primary role in determining cell and lineage commitment during development.
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            The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin.

            Takashi Nagano, Jennifer Mitchell, Lionel Sanz … (2008)
            A number of large noncoding RNAs (ncRNAs) epigenetically silence genes through unknown mechanisms. The Air ncRNA is imprinted--monoallelically expressed from the paternal allele. Air is required for allele-specific silencing of the cis-linked Slc22a3, Slc22a2, and Igf2r genes in mouse placenta. We show that Air interacts with the Slc22a3 promoter chromatin and the H3K9 histone methyltransferase G9a in placenta. Air accumulates at the Slc22a3 promoter in correlation with localized H3K9 methylation and transcriptional repression. Genetic ablation of G9a results in nonimprinted, biallelic transcription of Slc22a3. Truncated Air fails to accumulate at the Slc22a3 promoter, which results in reduced G9a recruitment and biallelic transcription. Our results suggest that Air, and potentially other large ncRNAs, target repressive histone-modifying activities through molecular interaction with specific chromatin domains to epigenetically silence transcription.
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              Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin.

              Bernhard Lehnertz, Yoshihide Ueda, Alwin A. H. A. Derijck … (2003)
              Histone H3 lysine 9 (H3-K9) methylation and DNA methylation are characteristic hallmarks of mammalian heterochromatin. H3-K9 methylation was recently shown to be a prerequisite for DNA methylation in Neurospora crassa and Arabidopsis thaliana. Currently, it is unknown whether a similar dependence exists in mammalian organisms. Here, we demonstrate a physical and functional link between the Suv39h-HP1 histone methylation system and DNA methyltransferase 3b (Dnmt3b) in mammals. Whereas in wild-type cells Dnmt3b interacts with HP1 alpha and is concentrated at heterochromatic foci, it fails to localize to these regions in Suv39h double null (dn) mouse embryonic stem (ES) cells. Consistently, the Suv39h dn ES cells display an altered DNA methylation profile at pericentric satellite repeats, but not at other repeat sequences. In contrast, H3-K9 trimethylation at pericentric heterochromatin is not impaired in Dnmt1 single- or Dnmt3a/Dnmt3b double-deficient ES cells. We also show that pericentric heterochromatin is not transcriptionally inert and can give rise to transcripts spanning the major satellite repeats. These data demonstrate an evolutionarily conserved pathway between histone H3-K9 methylation and DNA methylation in mammals. While the Suv39h HMTases are required to direct H3-K9 trimethylation and Dnmt3b-dependent DNA methylation at pericentric repeats, DNA methylation at centromeric repeats occurs independent of Suv39h function. Thus, our data also indicate a more complex interrelatedness between histone and DNA methylation systems in mammals. Both methylation systems are likely to be important in reinforcing the stability of heterochromatic subdomains and thereby in protecting genome integrity.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Cell
                Journal ID (iso-abbrev): Mol. Cell
                Title: Molecular Cell
                Publisher: Cell Press
                ISSN (Print): 1097-2765
                ISSN (Electronic): 1097-4164
                Publication date PMC-release: 04 November 2011
                Publication date (Print): 04 November 2011
                Volume: 44
                Issue: 3
                Pages: 361-372
                Affiliations
                [1 ]School of Life Sciences and Frontiers in Genetics Program, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
                [2 ]Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy
                [3 ]Department of Environmental Science, University of Naples 2, 81100 Caserta, Italy
                Author notes
                [∗ ]Corresponding author andrea.riccio@ 123456uunina2.it
                [∗∗ ]Corresponding author didier.trono@ 123456epfl.ch
                [4]

                These authors have contributed equally to this work

                [5]

                Present address: Centre de Regulació Genòmica and Universitat Pompeu Fabra, Parc de Recerca Biomèdica, 08003 Barcelona, Spain

                [6]

                Present address: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, 22184 Lund, Sweden

                Article
                Publisher ID: MOLCEL4048
                DOI: 10.1016/j.molcel.2011.08.032
                PMC ID: 3210328
                PubMed ID: 22055183
                SO-VID: 8f5b6ee6-4092-4bdd-a22b-faaa62b02c7f
                Copyright © © 2011 ELL & Excerpta Medica.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 20 April 2011
                Date revision received : 15 June 2011
                Date accepted : 15 August 2011
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Data availability:
                ScienceOpen disciplines: Molecular biology

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