Genome-wide expression profiling analysis of a Hmgn2 and Hmgn1/2 double knock out mutant mouse model. Mus musculus

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 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 necessary to retain wild type phenotypes. Our studies provide insights into mechanisms that maintain regulatory sites in chromatin and into functional compensation among nucleosome binding architectural proteins. Overall design: total RNA of brain, liver, spleen and thymus from homozygote Hmgn2-/- and homozygote double knock out Hmgn1-/-n2-/- was compared to the corresponding wild type RNA from the C57BL/6 strain