title: Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers.
abstract: DNase I hypersensitive sites (DHSs) are a hallmark of chromatin regions containing regulatory DNA such as enhancers and promoters; however, the factors affecting the establishment and maintenance of these sites are not fully understood. We now show that HMGN1 and HMGN2, nucleosome-binding proteins that are ubiquitously expressed in vertebrate cells, maintain the DHS landscape of mouse embryonic fibroblasts (MEFs) synergistically. Loss of one of these HMGN variants led to a compensatory increase of binding of the remaining variant. Genome-wide mapping of the DHSs in Hmgn1(-/-), Hmgn2(-/-), and Hmgn1(-/-)n2(-/-) MEFs reveals that loss of both, but not a single HMGN variant, leads to significant remodeling of the DHS landscape, especially at enhancer regions marked by H3K4me1 and H3K27ac. Loss of HMGN variants affects the induced expression of stress-responsive genes in MEFs, the transcription profiles of several mouse tissues, and leads to altered phenotypes that are not seen in mice lacking only one variant. We conclude that the compensatory binding of HMGN variants to chromatin maintains the DHS landscape, and the transcription fidelity and is necessary to retain wild-type phenotypes. Our study provides insight into mechanisms that maintain regulatory sites in chromatin and into functional compensation among nucleosome binding architectural proteins.
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Tao
authors.initials: T
authors.lastname: Deng
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20892, USA;
authors.forename: Z Iris
authors.initials: ZI
authors.lastname: Zhu
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Shaofei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Yuri
authors.initials: Y
authors.lastname: Postnikov
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20892, USA;
authors.forename: Di
authors.initials: D
authors.lastname: Huang
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Takashi
authors.initials: T
authors.lastname: Furusawa
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.affiliation: Molecular Nutritional Medicine, Technische Universität München, 85350 Freising, Germany; Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Developmental Genetics (IDG), 85764 Neuherberg, Germany;
authors.forename: Oana
authors.initials: O
authors.lastname: Amarie
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Developmental Genetics (IDG), 85764 Neuherberg, Germany;
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, 81377 Munich, Germany;
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, 81377 Munich, Germany;
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
authors.forename: Thure
authors.initials: T
authors.lastname: Adler
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany;
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20892, USA;
authors.forename: Arjan
authors.initials: A
authors.lastname: van der Velde
authors.affiliation: Neural Development Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20892, USA;
authors.forename: Ivan
authors.initials: I
authors.lastname: Ovcherenko
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20892, USA;
authors.forename: David
authors.initials: D
authors.lastname: Landsman
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Bustin
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D016000:Cluster Analysis; D003850:Deoxyribonuclease I / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D024001:HMGN Proteins / Q000235:genetics / Q000378:metabolism*; D024241:HMGN1 Protein / Q000235:genetics / Q000378:metabolism; D024242:HMGN2 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009707:Nucleosomes / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D002843:Chromatin; D024001:HMGN Proteins; D024241:HMGN1 Protein; D024242:HMGN2 Protein; D009707:Nucleosomes; D020033:Protein Isoforms; D003850:Deoxyribonuclease I