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

Deng, Tao; Zhu, Z Iris; Zhang, Shaofei; Postnikov, Yuri; Huang, Di; Horsch, Marion; Furusawa, Takashi; Beckers, Johannes; Rozman, Jan; Klingenspor, Martin; Amarie, Oana; Graw, Jochen; Rathkolb, Birgit; Wolf, Eckhard; Adler, Thure; Busch, Dirk H; Gailus-Durner, Valérie; Fuchs, Helmut; Hrabě de Angelis, Martin; van der Velde, Arjan; Tessarollo, Lino; Ovcherenko, Ivan; Landsman, David; Bustin, Michael;

Keywords

  • Animals
  • Binding Sites
  • Cell Line
  • Chromatin/ metabolism
  • Cluster Analysis
  • Deoxyribonuclease I/ metabolism
  • Enhancer Elements, Genetic
  • Gene Expression Profiling
  • Gene Knockout Techniques
  • HMGN Proteins/ genetics
  • HMGN Proteins/ metabolism
  • HMGN1 Protein/ genetics
  • HMGN1 Protein/ metabolism
  • HMGN2 Protein/ genetics
  • HMGN2 Protein/ metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Nucleosomes/ metabolism
  • Phenotype
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Isoforms
  • Stress, Physiological/ genetics

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