Epigenetic regulation of gene expression in response to various stimuli and factors is important for normal brain development and plasticity. It involves orchestration of numerous transcription factors which might be active only during development or in the adult nervous system. Mechanisms of epigenetic regulation include chromatin modifications (DNA methylation, post-translational histone modifications) and a fast-growing spectrum of small non-coding RNAs. Histone deacetylases (HDAC) which control gene silencing play an important role in gene regulation. The recently discovered mechanism of epigenetic regulation of a neuropeptidase neprilysin (NEP) and other genes by the amyloid precursor protein (APP) intracellular domain (AICD) and its dependence on the cell type and APP isoform expression suggest possibilities for selective manipulation of gene expression in neuronal cells. Our studies strongly indicate that in the process of gene regulation AICD competes with HDAC occupancy on the target gene promoters and treatment of cells or animals with HDAC inhibitors such as valproic acid results in up-regulation of NEP and TTR mRNA and protein levels and increased NEP activity leading to a reduction in total cellular amyloid (Aβ) peptide levels. Overexpression of APP in neuronal cells, in turn, affects the levels of HDAC mRNA expression, which extends the role of this protein in gene regulation. The development profile and specificity of NEP gene expression in the brain suggest the existence of a certain specificity in its epigenetic regulation in different brain structures and cell types. Understanding these mechanisms and modulating NEP expression in the brain by various classes of natural and synthetic compounds, including HDAC inhibitors or chromatin modulators, opens new avenues for developing preventive strategies in neurodegeneration and Alzheimer’s disease.
Наливаева Н. Н.