-
Molecular Aspects of Medicine Dec 2014Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death,... (Review)
Review
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
Topics: Disease; HMGB1 Protein; Health; Humans
PubMed: 25010388
DOI: 10.1016/j.mam.2014.05.001 -
International Journal of Molecular... Jan 2020Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can... (Review)
Review
Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can lead to disease. The high mobility group N (HMGN) is a family of nucleosome binding proteins that preferentially binds to chromatin regulatory sites including enhancers and promoters. HMGN proteins are ubiquitously expressed in all vertebrate cells potentially affecting chromatin function and epigenetic regulation in multiple cell types. Here, we review studies aimed at elucidating the biological function of HMGN proteins, focusing on their possible role in vertebrate development and the etiology of disease. The data indicate that changes in HMGN levels lead to cell type-specific phenotypes, suggesting that HMGN optimize epigenetic processes necessary for maintaining cell identity and for proper execution of specific cellular functions. This manuscript contains tables that can be used as a comprehensive resource for all the English written manuscripts describing research aimed at elucidating the biological function of the HMGN protein family.
Topics: Animals; Chromatin; Disease; Epigenesis, Genetic; Gene Expression Regulation, Developmental; HMGN Proteins; High Mobility Group Proteins; Humans; Mice; Promoter Regions, Genetic
PubMed: 31936777
DOI: 10.3390/ijms21020449 -
Nature Communications Nov 2022White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We...
White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We find that male mice lacking the nucleosome binding proteins HMGN1 and HMGN2 (DKO mice), show decreased body weight and inguinal WAT mass, but elevated food intake, WAT browning and energy expenditure. DKO white preadipocytes show reduced chromatin accessibility and lower FRA2 and JUN binding at Pparγ and Pparα promoters. White preadipocytes and mouse embryonic fibroblasts from DKO mice show enhanced rate of differentiation into brown-like adipocytes. Differentiating DKO adipocytes show reduced H3K27ac levels at white adipocyte-specific enhancers but elevated H3K27ac levels at brown adipocyte-specific enhancers, suggesting a faster rate of change in cell identity, from white to brown-like adipocytes. Thus, HMGN proteins function as epigenetic factors that stabilize white adipocyte cell identity, thereby modulating the rate of white adipose tissue browning and affecting energy metabolism in mice.
Topics: Male; Animals; Mice; Nucleosomes; Adipose Tissue, Brown; HMGN Proteins; Epigenesis, Genetic; Fibroblasts; Adipose Tissue, White; Adipocytes, Brown; Energy Metabolism
PubMed: 36435799
DOI: 10.1038/s41467-022-34964-5 -
Epigenetics & Chromatin Jun 2022Nucleosomal binding proteins, HMGN, is a family of chromatin architectural proteins that are expressed in all vertebrate nuclei. Although previous studies have...
BACKGROUND
Nucleosomal binding proteins, HMGN, is a family of chromatin architectural proteins that are expressed in all vertebrate nuclei. Although previous studies have discovered that HMGN proteins have important roles in gene regulation and chromatin accessibility, whether and how HMGN proteins affect higher order chromatin status remains unknown.
RESULTS
We examined the roles that HMGN1 and HMGN2 proteins play in higher order chromatin structures in three different cell types. We interrogated data generated in situ, using several techniques, including Hi-C, Promoter Capture Hi-C, ChIP-seq, and ChIP-MS. Our results show that HMGN proteins occupy the A compartment in the 3D nucleus space. In particular, HMGN proteins occupy genomic regions involved in cell-type-specific long-range promoter-enhancer interactions. Interestingly, depletion of HMGN proteins in the three different cell types does not cause structural changes in higher order chromatin, i.e., in topologically associated domains (TADs) and in A/B compartment scores. Using ChIP-seq combined with mass spectrometry, we discovered protein partners that are directly associated with or neighbors of HMGNs on nucleosomes.
CONCLUSIONS
We determined how HMGN chromatin architectural proteins are positioned within a 3D nucleus space, including the identification of their binding partners in mononucleosomes. Our research indicates that HMGN proteins localize to active chromatin compartments but do not have major effects on 3D higher order chromatin structure and that their binding to chromatin is not dependent on specific protein partners.
Topics: Chromatin; Epigenesis, Genetic; HMGN Proteins; Nucleosomes; Protein Binding
PubMed: 35761366
DOI: 10.1186/s13072-022-00457-4 -
Biochimica Et Biophysica Acta 2010High mobility group nucleosome-binding (HMGN) proteins are architectural non-histone chromosomal proteins that bind to nucleosomes and modulate the structure and... (Review)
Review
High mobility group nucleosome-binding (HMGN) proteins are architectural non-histone chromosomal proteins that bind to nucleosomes and modulate the structure and function of chromatin. The interaction of HMGN proteins with nucleosomes is dynamic and the proteins compete with the linker histone H1 chromatin-binding sites. HMGNs reduce the H1-mediated compaction of the chromatin fiber and facilitate the targeting of regulatory factors to chromatin. They modulate the cellular epigenetic profile, affect gene expression and impact the biological processes such as development and the cellular response to environmental and hormonal signals. Here we review the role of HMGN in chromatin structure, the link between HMGN proteins and histone modifications, and discuss the consequence of this link on nuclear processes and cellular phenotype.
Topics: Amino Acid Sequence; Animals; Chromatin; HMGN Proteins; Humans; Models, Biological; Molecular Sequence Data; Protein Binding; Templates, Genetic; Transcription, Genetic
PubMed: 19948260
DOI: 10.1016/j.bbagrm.2009.11.016 -
Biochimica Et Biophysica Acta 2010High mobility group N (HMGN) proteins are the only nuclear proteins known to specifically recognize the generic structure of the 147-bp nucleosome core particle. Both in... (Review)
Review
High mobility group N (HMGN) proteins are the only nuclear proteins known to specifically recognize the generic structure of the 147-bp nucleosome core particle. Both in vitro and in vivo experiments demonstrate that HMGN proteins are involved in epigenetic regulation by modulating chromatin structure and levels of posttranslational modifications of nucleosomal histones. Expression of HMGN proteins is developmentally regulated, and the loss or overexpression of these proteins can lead to developmental abnormalities. This review will focus on the role and on the possible molecular mechanism whereby HMGN proteins affect cellular differentiation and development.
Topics: Animals; Cell Differentiation; Gene Expression Regulation, Developmental; Growth and Development; HMGN Proteins; Humans
PubMed: 20123069
DOI: 10.1016/j.bbagrm.2009.11.011 -
Biochimica Et Biophysica Acta Jul 2012The HMGN family of proteins binds to nucleosomes without any specificity for the underlying DNA sequence. They affect the global and local structure of chromatin, as... (Review)
Review
The HMGN family of proteins binds to nucleosomes without any specificity for the underlying DNA sequence. They affect the global and local structure of chromatin, as well as the levels of histone modifications and thus play a role in epigenetic regulation of gene expression. This review focuses on the recent studies that provide new insights on the interactions between HMGN proteins, nucleosomes, and chromatin, and the effects of these interactions on epigenetic and transcriptional regulation. This article is part of a Special Issue entitled: Chromatin in time and space.
Topics: Amino Acid Sequence; Animals; Epigenesis, Genetic; HMGN Proteins; Histones; Humans; Nucleosomes; Protein Binding; Protein Processing, Post-Translational; Protein Structure, Tertiary; Transcription, Genetic
PubMed: 22326857
DOI: 10.1016/j.bbagrm.2012.01.013 -
Nucleic Acids Research Apr 2017An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not...
An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Line; Embryonic Stem Cells; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Female; HMGN Proteins; HMGN1 Protein; HMGN2 Protein; Histones; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Oligodendrocyte Transcription Factor 2; Oligodendroglia
PubMed: 27923998
DOI: 10.1093/nar/gkw1222 -
Nucleic Acids Research Sep 2016The activation of naïve B lymphocyte involves rapid and major changes in chromatin organization and gene expression; however, the complete repertoire of nuclear factors...
The activation of naïve B lymphocyte involves rapid and major changes in chromatin organization and gene expression; however, the complete repertoire of nuclear factors affecting these genomic changes is not known. We report that HMGN proteins, which bind to nucleosomes and affect chromatin structure and function, co-localize with, and maintain the intensity of DNase I hypersensitive sites genome wide, in resting but not in activated B cells. Transcription analyses of resting and activated B cells from wild-type and Hmgn(-/-) mice, show that loss of HMGNs dampens the magnitude of the transcriptional response and alters the pattern of gene expression during the course of B-cell activation; defense response genes are most affected at the onset of activation. Our study provides insights into the biological function of the ubiquitous HMGN chromatin binding proteins and into epigenetic processes that affect the fidelity of the transcriptional response during the activation of B cell lymphocytes.
Topics: Animals; B-Lymphocytes; Chromatin; Deoxyribonuclease I; Epigenesis, Genetic; Gene Expression Regulation; HMGN Proteins; HMGN1 Protein; HMGN2 Protein; Lymphocyte Activation; Male; Mice; Nucleosomes; Promoter Regions, Genetic; Protein Binding; Regulatory Sequences, Nucleic Acid; Spleen
PubMed: 27112571
DOI: 10.1093/nar/gkw323 -
Nucleic Acids Research May 2011High mobility group N (HMGN) is a family of intrinsically disordered nuclear proteins that bind to nucleosomes, alters the structure of chromatin and affects...
High mobility group N (HMGN) is a family of intrinsically disordered nuclear proteins that bind to nucleosomes, alters the structure of chromatin and affects transcription. A major unresolved question is the extent of functional specificity, or redundancy, between the various members of the HMGN protein family. Here, we analyze the transcriptional profile of cells in which the expression of various HMGN proteins has been either deleted or doubled. We find that both up- and downregulation of HMGN expression altered the cellular transcription profile. Most, but not all of the changes were variant specific, suggesting limited redundancy in transcriptional regulation. Analysis of point and swap HMGN mutants revealed that the transcriptional specificity is determined by a unique combination of a functional nucleosome-binding domain and C-terminal domain. Doubling the amount of HMGN had a significantly larger effect on the transcription profile than total deletion, suggesting that the intrinsically disordered structure of HMGN proteins plays an important role in their function. The results reveal an HMGN-variant-specific effect on the fidelity of the cellular transcription profile, indicating that functionally the various HMGN subtypes are not fully redundant.
Topics: Amino Acid Sequence; Animals; HMGN Proteins; Mice; Mice, Knockout; Molecular Sequence Data; Mutation; Sequence Homology, Amino Acid; Transcription, Genetic
PubMed: 21278158
DOI: 10.1093/nar/gkq1343