The current proposal was inspired by our recently applied methodology for whole-genome analysis of regulatory chromatin landscape and genetic-epigenetic interactions in human brain neurons. We hypothesize that, during aging, the active chromatin in human cortical neurons is gradually modified in a subset of chromosomal loci. These chromatin modifications lead to an altered epigenetic state of activity of certain genes, contributing to vulnerability of aging neurons in brain regions vulnerable to Alzheimer's disease (AD) - related degeneration signals. We plan to identify these aging-specific neuro-chromatin signatures marked by modified histones specific for active gene promoters and active gene enhancers. We will apply ChIP-seq technology for whole-genome analysis of neuronal chromatin extracted from brain regions susceptible to AD both in a cohort of non-demented individuals stratified by age and in AD patients. We will search whether the group of genes epigenetically modified in aging and AD neurons is enriched in any gene ontology category and specific biological pathway. The genes with altered epigenetic signatures will be tested further whether they overlap with the genetic risk loci for AD and AD-related traits. We suggest that the genes for signal transducers, especially for genes with stress-response and immune functions, are targets for epigenetic modifications in aging- neurons underlying AD neurodegeneration. These predictions will be tested in animal models by direct knockdown of gene activity by a novel type of siRNA therapeutic compounds.
The objective of this project is (i) to provide the first comparative map of active chromatin loci in cerebral neurons of elderly and middle age- versus young age- individuals and in Alzheimer's Disease (AD) patients; (ii) to identify genes epigenetically modified in aging neurons in brain regions vulnerable to AD pathology; (iii) to establish genetic links between aging- and stress- related and AD-related pathology; (iiii) to provide evidence that by down-regulation of genes epigenetically up-regulated in aging neurons we can modulate AD-pathology.
| Babenko, Vladimir N; Afonnikov, Dmitry A; Ignatieva, Elena V et al. (2018) Haplotype analysis of APOE intragenic SNPs. BMC Neurosci 19:16 |
