Membrane depolarization controls long lasting adaptive neuronal changes in brain physiology and pathology. Such responses are believed to be gene expression-dependent. Notably, however, only a couple of gene repressors active in nondepolarized neurons have been described. In this study, we show that in the unstimulated rat hippocampus in vivo, as well as in the nondepolarized brain neurons in primary culture, the transcriptional regulator Yin Yang 1 (YY1) is bound to the proximal Mmp-9 promoter and strongly represses Mmp-9 transcription. Furthermore, we demonstrate that monoubiquitinated and CtBP1 (C-terminal binding protein 1)-bound YY1 regulates Mmp-9 mRNA synthesis in rat brain neurons controlling its transcription apparently via HDAC3-dependent histone deacetylation. In conclusion, our data suggest that YY1 exerts, via epigenetic mechanisms, a control over neuronal expression of MMP-9. Because MMP-9 has recently been shown to play a pivotal role in physiological and pathological neuronal plasticity, YY1 may be implicated in these phenomena as well.Neuronal depolarization is important not only for a transmission of information throughout the nervous system but also for an initiation of adaptive neuronal responses to incoming stimuli. Examples of the adaptive changes are long term potentiation and kindling-evoked epileptogenesis believed to underlie physiological (such as learning and memory) and pathological neuronal plasticity, respectively. These long lasting adaptive changes have been linked to an activation of gene expression. Indeed, a number of depolarization-driven gene responses were described over the last 20 years, and in almost all cases inducible transcription factors, like cAMP-response element-binding protein, Elk-1, AP-1, Egrs, etc. (for review see Ref. 1), were found to be responsible for the increased gene expression. However, it is also conceivable to consider a repression of transcription, in addition to its activation, as a means to drive depolarization-evoked gene expression. So far only a very limited number of such repressive molecules has been discovered (2-4).In this study we set out to search for these transcriptional repressors. We focused on a regulation of Mmp-9 that codes for an extracellular matrix protease involved in physiological and pathological extracellular matrix remodeling. Aberrant, and usually excessive, Mmp-9 expression has been linked to numerous disorders of the central nervous system (5-7) as well as other devastating diseases such as tumors (8, 9). Hence, detailed knowledge of its transcriptional repression is of great importance for an understanding of those pathologies and for a potential development of novel therapeutic approaches.Our previous reports have shown that in the nondepolarized rat brain MMP-9 3 is predominantly expressed in neurons (10 -12). However, its expression levels in those cells are very low, which points toward a presence of an efficient mechanism(s) repressing its transcription in unstimulated neurons (10).Molecular mechanisms directly con...

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Yin Yang 1 (YY1) is a ubiquitous transcription factor belonging to Polycomb group proteins. Its expression patterns in the adult brain have not been before clearly elucidated. Using immunohistochemical stainings, we show a distribution of YY1 protein throughout the adult rodent brain. Furthermore, we characterize a cellular localization of YY1 protein and mRNA in the adult rat hippocampus. We have found that YY1 is expressed in all major brain regions, although not ubiquitously in all cells, and its expression levels vary significantly depending on the brain structure. In most of the regions YY1 is not very abundant, but in the olfactory bulb, cerebellar cortex, hippocampus, cerebral cortex, wall of the lateral ventricle and rostral migratory stream intense YY1 staining is observed. In the rat hippocampus, YY1 protein and mRNA are very strongly expressed in neurons, and to a lesser extent in oligodendroglia and microglia. In contrast, we have not detected YY1 protein in astrocytes, which are the most abundant component of hippocampal glia. Moreover, we show that in the adult rodent brain, YY1 is expressed exclusively in the cell nuclei, except of a molecular layer of cerebellar cortex, where it is also present in the cytoplasm. Interestingly, YY1 staining is accumulated in a form of granules in cell nuclei of different types of brain cells. Thus, our data demonstrate that in the adult rodent brain YY1 is predominantly localized to neurons.