HMGN1 and HMGN2 are ubiquitously expressed nucleosome-binding proteins. The study showed that the two genes synergistically maintain the DNase I hypersensitive sites (DHSs) landscape of mouse embryonic fibroblasts (MEFs). DHSs are characteristic for chromatin regions containing regulatory DNA elements. 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 revealed that loss of both, but not a single HMGN variant, leads to significant remodeling of the DHSs landscape.
Hmgn1-/-, Hmgn2-/- and Hmgn1-/-n2-/- knock-out (ko) mice were systematically analyzed in the German Mouse Clinic. The Hmgn1-/-n2-/- double ko mice showed significantly more altered phenotypes in the tested organ systems than either Hmgn1-/- or Hmgn2-/- mice alone. For Hmgn1-/-n2-/- mice, altered parameters were found in the metabolic screening (increased food intake but decreased body mass), clinical chemistry analysis (changes in the levels albumin, alpha amylase activity, triglyceride, cholesterol, and insulin levels), in immunology (changes in the distribution of leukocyte subpopulations) and in the eye screen (reduced corneal thickness, significantly enlarged eye axial lengths and increased number of the fundic main blood vessels). Some of these phenotypes were also observed in single gene mutants, but most only were present when both Hmgn genes were inactivated.
Thus, the phenotypic analyses indicate that loss of both HMGN1 and HMGN2 lead to more altered phenotypes then loss of only HMGN1 or HMGN2, a finding that is in general agreement with the compensatory binding of HMGN variants to chromatin and with the more severe changes in the DHSs landscape of Hmgn1-/-n2-/- mice.
Tao Deng, Z. Iris Zhu, Shaofei Zhang, Yuri Postnikov, Di Huang, Marion Horsch, Takashi Furusawa, Johannes Beckers, Jan Rozman, Martin Klingenspor, Oana Amarie, Jochen Graw, Birgit Rathkolb, Eckhard Wolf, Thure Adler, Dirk H. Busch, Valerie Galius-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Arjan van der Velde, Lino Tessarollo, Ivan Ovcherenko, David Landsman, Michael Bustin (2015): Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers. Genome Res. 2015 Sep;25(9):1295-308. doi: 10.1101/gr.192229.115.