title: Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells.
abstract: The H3K9me3-specific histone methyltransferase Setdb1 impacts on transcriptional regulation by repressing both developmental genes and retrotransposons. How impaired retrotransposon silencing may lead to developmental phenotypes is currently unclear. Here, we show that loss of Setdb1 in pro-B cells completely abrogates B cell development. In pro-B cells, Setdb1 is dispensable for silencing of lineage-inappropriate developmental genes. Instead, we detect strong derepression of endogenous murine leukemia virus (MLV) copies. This activation coincides with an unusual change in chromatin structure, with only partial loss of H3K9me3 and unchanged DNA methylation, but strongly increased H3K4me3. Production of MLV proteins leads to activation of the unfolded protein response pathway and apoptosis. Thus, our data demonstrate that B cell development depends on the proper repression of retrotransposon sequences through Setdb1.
authors.affiliation: Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, 82152 Planegg-Martinsried, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pasquarella
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Ebert
authors.affiliation: Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, 82152 Planegg-Martinsried, Germany.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pereira de Almeida
authors.affiliation: Ludwig Maximilians University, Institute for Immunology, 80336 München, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Hinterberger
authors.affiliation: Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, 82152 Planegg-Martinsried, Germany.
authors.forename: Maryam
authors.initials: M
authors.lastname: Kazerani
authors.affiliation: Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, 82152 Planegg-Martinsried, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nuber
authors.affiliation: Helmholtz Zentrum München, Institute of Molecular Immunology, 81377 München, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Ellwart
authors.affiliation: Ludwig Maximilians University, Institute for Immunology, 80336 München, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.affiliation: Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, 82152 Planegg-Martinsried, Germany gunnar.schotta@med.uni-muenchen.de.
authors.forename: Gunnar
authors.identifier: 0000-0003-4940-6135
authors.initials: G
authors.lastname: Schotta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D020869:Gene Expression Profiling; D020868:Gene Silencing; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D018626:Retroelements / Q000235:genetics*; D014158:Transcription, Genetic; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D006657:Histones; D018626:Retroelements; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; D008239:Lysine
keywords: Heterochromatin; Mouse; Retrotransposon; Setdb1; Unfolded protein response