title: Activation of Endogenous Retroviruses in Dnmt1(-/-) ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA.
abstract: Repression of endogenous retroviruses (ERVs) in mammals involves several epigenetic mechanisms. Acute loss of the maintenance methyltransferase Dnmt1 induces widespread DNA demethylation and transcriptional activation of ERVs, including CpG-rich IAP (intracisternal A particle) proviruses. Here, we show that this effect is not due simply to a loss of DNA methylation. Conditional deletions reveal that both Dnmt1 and Np95 are essential for maintenance DNA methylation. However, while IAPs are derepressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these ERVs remain silenced when Np95 is deleted alone or in combination with Dnmt1. This paradoxical phenotype results from an ectopic interaction between NP95 and the H3K9 methyltransferase SETDB1. Normally, SETDB1 maintains silencing of IAPs, but in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA transiently disrupts SETDB1-dependent H3K9me3 deposition. Thus, our observations reveal an unexpected antagonistic interplay between two repressive pathways involved in retroviral silencing in mammalian cells.
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Jafar
authors.initials: J
authors.lastname: Sharif
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takaho A
authors.initials: TA
authors.lastname: Endo
authors.affiliation: Department of Technology Development, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Karimi
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Katsuyama
authors.affiliation: Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Preeti
authors.initials: P
authors.lastname: Goyal
authors.affiliation: Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Brind'Amour
authors.affiliation: Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24060, USA.
authors.forename: Ming-An
authors.initials: MA
authors.lastname: Sun
authors.affiliation: Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24060, USA; Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24060, USA.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ishikura
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mizutani-Koseki
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Department of Technology Development, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Cellular Memory Laboratory, RIKEN, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shinkai
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
authors.affiliation: Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24060, USA; Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24060, USA.
authors.forename: Hehuang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: mlorincz@mail.ubc.ca.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lorincz
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address: haruhiko.koseki@riken.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D020077:Endogenous Retroviruses / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D007426:Genes, Intracisternal A-Particle; D056426:Genetic Loci; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D000072417:Protein Domains; D014327:Trophoblasts / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014775:Virus Activation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse; D008239:Lysine