Molecular mechanisms regulating the astrocyte-specific expression of the human serpin genes at chromosome 14Q32.1

Selective expression of certain genes in a given organ, dictates its specific functions. Although, mechanisms controlling the tissue-specific gene expression have been extensively studied over the years, the astrocyte-specific gene expression in the brain is not clearly understood. Here, we have identified a regulatory mechanism that enables the astrocyte-specific expression of the alpha 1-antichymotrypsin (ACT) in the brain. Since the expression of ACT is upregulated in the brains of patients suffering from Alzheimer's disease (AD), an understanding of its transcriptional regulation may provide important insights required for the future treatment of AD.; The ACT gene is localized within the distal serpin subcluster containing three additional serine protease inhibitor (serpin) genes. While all of these genes are expressed within hepatocytes, only the ACT gene is expressed in the brain by astrocytes. We propose the mechanism that governs the differential expression of the serpin genes in astrocytes. The analysis of this subclusters hypersensitivity to DNase I, its restriction enzyme accessibility, and "histone code", demonstrated that the ACT gene is localized to "decondensed" chromatin, whereas the other genes within this cluster are localized to "condensed" chromatin. In contrast, all of these genes are localized to decondensed, active chromatin in hepatocytes. These differences in chromatin structure, between astrocytes and hepatocytes, determine the tissue-specific expression of the distal serpin genes. Different chromatin structures are, in turn, determined by the tissue-specific transcription factors. Here, we propose that both activator protein 1 (AP-1) and nuclear factor I (NFI) are indispensable for the expression of the ACT gene in astrocytes and glioma cells. Moreover, we demonstrate that both AP-1 and NFI are indispensable for the expression of glial fibrillary acidic protein (GFAP), which is an astrocyte specific marker protein.; Overall, we demonstrate for the first time the tissue-specific molecular mechanism which determines expression of the ACT and GFAP genes that may also apply to other genes specifically expressed in astrocytes. We propose that both AP-1 and NFI cooperate in an astrocyte-specific manner to localize the expression of certain genes within the central nervous system.