We are investigating the role of chromosomal proteins in determining the structure and regulating the function of chromatin. Transgenic animals, cell free chromatin assembly systems, and in vitro- reconstitution assays are used to determine the role of chromosomal proteins HMGN1 and HMGN2 in chromatin structure and nuclear function. These two proteins are the only nonhistone structural proteins known to specifically associate with the nucleosome core, which is the building block of the chromatin fiber. We found that these proteins unfold the higher order chromatin structure thereby facilitating access to the underlying DNA sequence and facilitating the orderly progression of various DNA-dependent actitvitis in the context of chromatin. By confocal immunofluorescence we find that the HMGN2 protein colocalizes with nascent transcripts. This colocalization is dynamic and reversible and may be regulated by post-translational modifications. We also find that the proteins are not always associated with DNA and actively shuttle between the nucleus and the cytoplasm, in a cell-cycle dependent manner. This shuttling is affected by phoshporylation of specific residues in the proteins. Our studies suggest that the intracellular trafficking and localization of these proteins is in part regulated be specific postranslational modifications. We also find that the histone acetyl transferase and transciptional coactivator p300, acetylates HMGN proteins at multiple sites. All of the sites, which were mapped both in vivo and in vitro, are in evolutionarily conserved domains suggesting that this modification may be an important aspect of the celular function of the protein. We have also devised a new strategy for characterizing the parameters governing the binding of HMGs and other proteins to chromatin subunits. These studies provide novel insights into the molecular mechanisms whereby specific nuclear proteins regulate the strucure of chromatin and affect numerous DNA-related activities in the nucleus of the cell. We have created knock out mouse for HMGN1. This mouse displays pleiotropic effects on gene regualtion and cells derived from the mouse have tumorigenic and have diminshed ability to respond to stress. The mice have an altered hair growth cycle and display changes in skin growth chracteristics. These properties are the basis of a paten tapplication which proposes to use the HMGN1 pathway to affect wound healing and perhaps affect stm cell growth. The knock-out mice and tissues derived from it provide new investigative approaches for studies on the role of chromatin in gene regulation and cancer etiology.
| Subramanian, Mangalam; Gonzalez, Rhiannon W; Patil, Hemangi et al. (2009) The nucleosome-binding protein HMGN2 modulates global genome repair. FEBS J 276:6646-57 |
| Lucey, Michelle M; Wang, Yan; Bustin, Michael et al. (2008) Differential expression of the HMGN family of chromatin proteins during ocular development. Gene Expr Patterns 8:433-7 |
| Gerlitz, Gabi; Livnat, Idit; Ziv, Carmit et al. (2007) Migration cues induce chromatin alterations. Traffic 8:1521-9 |
| Hock, Robert; Furusawa, Takashi; Ueda, Tetsuya et al. (2007) HMG chromosomal proteins in development and disease. Trends Cell Biol 17:72-9 |
| Yang, De; Chen, Qian; Yang, Huan et al. (2007) High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol 81:59-66 |
| Birger, Yehudit; Davis, Janine; Furusawa, Takashi et al. (2006) A role for chromosomal protein HMGN1 in corneal maturation. Differentiation 74:19-29 |
| Ueda, Tetsuya; Postnikov, Yuri V; Bustin, Michael (2006) Distinct domains in high mobility group N variants modulate specific chromatin modifications. J Biol Chem 281:10182-7 |
| Furusawa, Takashi; Lim, Jae-Hwan; Catez, Frederic et al. (2006) Down-regulation of nucleosomal binding protein HMGN1 expression during embryogenesis modulates Sox9 expression in chondrocytes. Mol Cell Biol 26:592-604 |
| Catez, Frederic; Ueda, Tetsuya; Bustin, Michael (2006) Determinants of histone H1 mobility and chromatin binding in living cells. Nat Struct Mol Biol 13:305-10 |
| Postnikov, Yuri V; Belova, Galina I; Lim, Jae-Hwan et al. (2006) Chromosomal protein HMGN1 modulates the phosphorylation of serine 1 in histone H2A. Biochemistry 45:15092-9 |
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