RESUMO
Single nucleotide polymorphisms (SNPs) are the most common type of variation in the human genome. The vast majority of SNPs identified in the human genome do not have any effect on the phenotype; however, some can lead to changes in the function of a gene or the level of its expression. Most SNPs associated with certain traits or pathologies are mapped to regulatory regions of the genome and affect gene expression by changing transcription factor binding sites. In recent decades, substantial effort has been invested in searching for such regulatory SNPs (rSNPs) and understanding the mechanisms by which they lead to phenotypic differences, primarily to individual differences in susceptibility to diseases and in sensitivity to drugs. The development of the NGS (next-generation sequencing) technology has contributed not only to the identification of a huge number of SNPs and to the search for their association (genome-wide association studies, GWASs) with certain diseases or phenotypic manifestations, but also to the development of more productive approaches to their functional annotation. It should be noted that the presence of an association does not allow one to identify a functional, truly disease-associated DNA sequence variant among multiple marker SNPs that are detected due to linkage disequilibrium. Moreover, determination of associations of genetic variants with a disease does not provide information about the functionality of these variants, which is necessary to elucidate the molecular mechanisms of the development of pathology and to design effective methods for its treatment and prevention. In this regard, the functional analysis of SNPs annotated in the GWAS catalog, both at the genome-wide level and at the level of individual SNPs, became especially relevant in recent years. A genome-wide search for potential rSNPs is possible without any prior knowledge of their association with a trait. Thus, mapping expression quantitative trait loci (eQTLs) makes it possible to identify an SNP for which - among transcriptomes of homozygotes and heterozygotes for its various alleles - there are differences in the expression level of certain genes, which can be located at various distances from the SNP. To predict rSNPs, approaches based on searches for allele-specific events in RNA-seq, ChIP-seq, DNase-seq, ATAC-seq, MPRA, and other data are also used. Nonetheless, for a more complete functional annotation of such rSNPs, it is necessary to establish their association with a trait, in particular, with a predisposition to a certain pathology or sensitivity to drugs. Thus, approaches to finding SNPs important for the development of a trait can be categorized into two groups: (1) starting from data on an association of SNPs with a certain trait, (2) starting from the determination of allele-specific changes at the molecular level (in a transcriptome or regulome). Only comprehensive use of strategically different approaches can considerably enrich our knowledge about the role of genetic determinants in the molecular mechanisms of trait formation, including predisposition to multifactorial diseases.
RESUMO
Oligodendrocytes are one type of glial cells responsible for myelination and providing trophic support for axons in the central nervous system of vertebrates. Thanks to myelin, the speed of electrical-signal conduction increases several hundred-fold because myelin serves as a kind of electrical insulator of nerve f ibers and allows for quick saltatory conduction of action potentials through Ranvier nodes, which are devoid of myelin. Given that different parts of the central nervous system are myelinated at different stages of development and most regions contain both myelinated and unmyelinated axons, it is obvious that very precise mechanisms must exist to control the myelination of individual axons. As they go through the stages of specif ication and differentiation - from multipotent neuronal cells in the ventricular zone of the neural tube to mature myelinating oligodendrocytes as well as during migration along blood vessels to their destination - cells undergo dramatic changes in the pattern of gene expression. These changes require precisely spatially and temporally coordinated interactions of various transcription factors and epigenetic events that determine the regulatory landscape of chromatin. Chromatin remodeling substantially affects transcriptional activity of genes. The main component of chromatin is the nucleosome, which, in addition to the structural function, performs a regulatory one and serves as a general repressor of genes. Changes in the type, position, and local density of nucleosomes require the action of specialized ATPdependent chromatin-remodeling complexes, which use the energy of ATP hydrolysis for their activity. Mutations in the genes encoding proteins of the remodeling complexes are often accompanied by serious disorders at early stages of embryogenesis and are frequently identif ied in various cancers. According to the domain arrangement of the ATP-hydrolyzing subunit, most of the identif ied ATP-dependent chromatin-remodeling complexes are classif ied into four subfamilies: SWI/SNF, CHD, INO80/SWR, and ISWI. In this review, we discuss the roles of these subunits of the different subfamilies at different stages of oligodendrogenesis.
