Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers
- Tao Deng1,12,
- Z. Iris Zhu2,12,
- Shaofei Zhang1,
- Yuri Postnikov1,
- Di Huang2,
- Marion Horsch3,
- Takashi Furusawa1,
- Johannes Beckers3,4,5,
- Jan Rozman3,5,
- Martin Klingenspor6,7,
- Oana Amarie3,8,
- Jochen Graw3,8,
- Birgit Rathkolb3,5,9,
- Eckhard Wolf9,
- Thure Adler3,
- Dirk H. Busch10,
- Valérie Gailus-Durner3,
- Helmut Fuchs3,
- Martin Hrabě de Angelis3,4,5,
- Arjan van der Velde2,13,
- Lino Tessarollo11,
- Ivan Ovcherenko2,
- David Landsman2 and
- Michael Bustin1
- 1Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
- 2Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20892, USA;
- 3German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
- 4Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan, Germany;
- 5German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany;
- 6Molecular Nutritional Medicine, Technische Universität München, 85350 Freising, Germany;
- 7Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising, Germany;
- 8Institute of Developmental Genetics (IDG), 85764 Neuherberg, Germany;
- 9Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, 81377 Munich, Germany;
- 10Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany;
- 11Neural Development Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, USA
- Corresponding author: bustinm{at}mail.nih.gov
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↵12 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.192229.115.
- Received March 17, 2015.
- Accepted July 7, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.