High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner

Kugler, Jamie E.; Horsch, Marion; Huang, Di; Furusawa, Takashi; Rochman, Mark; Garrett, Lillian; Becker, Lore; Bohla, Alexander; Hölter, Sabine M.; Prehn, Cornelia; Rathkolb, Birgit; Rácz, Ildikó; Aguilar-Pimentel, Juan Antonio; Adler, Thure; Adamski, Jerzy; Beckers, Johannes; Busch, Dirk H.; Eickelberg, Oliver; Klopstock, Thomas; Ollert, Markus; Stöger, Tobias; Wolf, Eckhard; Wurst, Wolfgang; Yildirim, Ali Önder; Zimmer, Andreas; Gailus‐Durner, Valérie; Fuchs, Helmut; Angelis, Martin Hrabé de; Garfinkel, Benjamin P.; Orly, Joseph; Ovcharenko, Ivan; Bustin, Michael

doi:10.1074/jbc.m113.463315

Cited by 39 publications

(53 citation statements)

References 69 publications

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“…6E-H) or between the four tissues taken from a mouse line (Fig. 6I-K), reinforcing previous findings indicating tissue-specific and HMGN variant-specific effects on transcription (Kugler et al 2013). In addition to examining the genes with significant changes in gene expression, we also analyzed the effect of HMGN loss on cellular transcription pathways, disregarding the magnitude of change in the expression levels of individual genes.…”

Section: Wwwgenomeorgsupporting

confidence: 74%

“…−/− , Hmgn2 −/− , and Hmgn1 −/− n2 −/− knockout mice Hmgn1 −/− mice, lacking exons 2-4 of the gene, were previously described (Birger et al 2003;Kugler et al 2013 constructed by a recombinogenic cloning strategy (Liu et al 2003) with a murine bacterial artificial chromosome clone, RP23-31L13. The vector was constructed to remove the entire gene, encompassing exons 1-6 (Supplemental Fig.…”

Section: Generation Of Hmgn1mentioning

confidence: 99%

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Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

et al. 2015

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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 wildtype phenotypes. Our study provides insight into mechanisms that maintain regulatory sites in chromatin and into functional compensation among nucleosome binding architectural proteins. [Supplemental material is available for this article.]Tissue-and developmental-specific gene expression is facilitated by the binding of transcription factors to unique DNA sequences at regulatory sites in chromatin, such as enhancers and promoters. At these sites, the organization of the nucleosomes is altered, rendering the DNA more accessible to regulatory factors and hypersensitive to digestion by various nucleases including DNase I. DNase I hypersensitive sites (DHSs) are a hallmark of chromatin regions containing regulatory DNA and are used to identify regulatory sites in chromatin. The DHSs chromatin landscape is cell-type specific and dynamic, reflecting changes in the cellular transcription profile occurring during development, or as a consequence of genomic changes leading to altered cellular phenotypes (Gross and Garrard 1988;Boyle et al. 2008;Thurman et al. 2012;Calo and Wysocka 2013;Stergachis et al. 2013).The molecular mechanisms that establish and maintain DHSs and their role in gene expression are key questions in chromatin biology. DHSs are established by the combined action of transcription factors that bind dynamically to specific DNA sequences and 12 These authors contributed equally to this work.

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Section: Wwwgenomeorgsupporting

confidence: 74%

Section: Generation Of Hmgn1mentioning

confidence: 99%

Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

et al. 2015

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“…Loss of HMGN5 function in the brain induces transcriptional changes in genes implicated in nervous system development and cell morphogenesis (15). As observed for HMGN1 (49), we also detect high HMGN5 expression levels in neurogenic areas of the mouse brain (F. Moretti and C. Rolando, unpublished observations).…”

Section: Discussionsupporting

confidence: 53%

“…Since HMGN5 modulates the transcriptome of different cell types and organs (15,33), we performed transcriptome analysis of N1E-115 cells transfected with Hmgn5 small interfering RNAs (siRNAs) and compared them to N1E-115 cells transfected with control (ctrl) siRNAs. To identify transcripts specifically linked to neurite outgrowth, we first differ- entiated our cells by serum starvation and detached and allowed them to extend neurites for 24 h on a laminin substrate.…”

Section: Resultsmentioning

confidence: 99%

“…Its structure comprises an N-terminal nuclear localization signal, a nucleosome binding domain (NBD), and a C-terminal acidic tail that is able to interact with the histone H1 C-terminal tail (14). In animals with impaired HMGN5 function, the transcriptional profiles of several organs, including brain, spleen, liver, and thymus, are affected (15). Although little is known about HMGN5 physiological functions, it has been suggested that HMGN5 might control cellular differentiation, glutathione metabolism, tumor progression, and cardiac function (14,16,17).…”

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Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth

Moretti

Rolando

Winker

et al. 2015

Molecular and Cellular Biology

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f Neurons exploit local mRNA translation and retrograde transport of transcription factors to regulate gene expression in response to signaling events at distal neuronal ends. Whether epigenetic factors could also be involved in such regulation is not known. We report that the mRNA encoding the high-mobility group N5 (HMGN5) chromatin binding protein localizes to growth cones of both neuronlike cells and of hippocampal neurons, where it has the potential to be translated, and that HMGN5 can be retrogradely transported into the nucleus along neurites. Loss of HMGN5 function induces transcriptional changes and impairs neurite outgrowth, while HMGN5 overexpression induces neurite outgrowth and chromatin decompaction; these effects are dependent on growth cone localization of Hmgn5 mRNA. We suggest that the localization and local translation of transcripts coding for epigenetic factors couple the dynamic neuronal outgrowth process with chromatin regulation in the nucleus.

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Combining Rapid Data Independent Acquisition and CRISPR Gene Deletion for Studying Potential Protein Functions: A Case of HMGN1

Mehnert

et al. 2019

Proteomics

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CRISPR‐Cas gene editing holds substantial promise in many biomedical disciplines and basic research. Due to the important functional implications of non‐histone chromosomal protein HMG‐14 (HMGN1) in regulating chromatin structure and tumor immunity, gene knockout of HMGN1 is performed by CRISPR in cancer cells and the following proteomic regulation events are studied. In particular, DIA mass spectrometry (DIA‐MS) is utilized, and more than 6200 proteins (protein‐ FDR 1%) and more than 82 000 peptide precursors are reproducibly measured in the single MS shots of 2 h. HMGN1 protein deletion is confidently verified by DIA‐MS in all of the clone‐ and dish‐ replicates following CRISPR. Statistical analysis reveals 147 proteins change their expressions significantly after HMGN1 knockout. Functional annotation and enrichment analysis indicate the deletion of HMGN1 induces histone inactivation, various stress pathways, remodeling of extracellular proteomes, cell proliferation, as well as immune regulation processes such as complement and coagulation cascade and interferon alpha/ gamma response in cancer cells. These results shed new lights on the cellular functions of HMGN1. It is suggested that DIA‐MS can be reliably used as a rapid, robust, and cost‐effective proteomic‐screening tool to assess the outcome of the CRISPR experiments.

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High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner

Cited by 39 publications

References 69 publications

Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth

Combining Rapid Data Independent Acquisition and CRISPR Gene Deletion for Studying Potential Protein Functions: A Case of HMGN1

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