Читать книгу Algorithms in Bioinformatics - Paul A. Gagniuc - Страница 16

In multicellular organisms, every cell type usually contains the same DNA information; however, it exhibits a different phenotype. What determines this behavior ? Double-stranded DNA molecules of eukaryotic organisms are folded and distributed into chromosomes, which take the form of chromatin (DNA, histone proteins, and non-histone proteins). The basic organization of chromatin consists of filaments made of repetitive units called nucleosomes. Each nucleosome consists of eight histone proteins (i.e. type H2A, H2B, H3, and H4) that wrap ∼146 base pairs (bp) of double-stranded DNA (Figure 1.3a). Nucleosomes are connected to each other by 10–80 bp of DNA associated with linker histone H1 that wraps another 20 bp [30]. This basic form of chromatin self-assembles into higher orders of organization. Inside the cell nucleus, these higher orders of chromatin organization include the chromatin fibers, the fractal globules, and reach a final level of organization, namely the chromosomal territories [31, 32]. Chromatin is a highly dynamic three-dimensional structure, which self-arranges differently from one cell type to another, thus, establishing and maintaining the cell identity [31, 33, 34]. But what determines these chromatin self-arrangements? The predispositions for self-arrangements are determined in advance by chromatin remodelers [35]. Among the chromatin remodelers, two main families of enzymes are heavily involved in the global chromatin organization during the cell cycle, namely acetyltransferases and deacetylases. These enzymes make changes to the histone tails of the nucleosomes (histone tails are amino acid chains that extend from the nucleosomal core – Figure 1.3a). Histone tail acetylation on the nucleosomes leads to a relaxed form of chromatin, which subsequently allows transcription factors (TF) to gain access to their target genes (euchromatin). Histone deacetylation leads to a higher-order folding of nucleosomal arrays, which in turn form a dense chromatin structure that is inaccessible to the transcription machinery (heterochromatin) [36]. Thus, patterns of histone acetylation and deacetylation along the chromatin filaments dictate the initial chromatin folding and unfolding inside the cell nucleus and consequently the activity of a specific subset of genes [37]. These acetylation–deacetylation mechanisms are combined (among others) with DNA methylation mechanisms, which lead to a gradual and stable inactivation of certain genes over several cell generations (a topic discussed in other chapters). Nevertheless, the global distribution of chromatin is established immediately after the cell division and exposes a subset of genes specific to the cell type. The DNA regions that contain the genes that are part of the cell type subset are positioned more toward the center of the cell nucleus in the relaxed volume of the chromatin (called euchromatin) [31]. In contrast, genes outside the cell-type subset are distributed in the condensed volumes of chromatin (called heterochromatin) that are usually positioned toward the inner part of the nuclear membrane (Figure 1.2c–f).

Figure 1.2 Ultrastructural images of adipocyte cells from Bos taurus (Cattles). Adipocytes especially show how tolerant and adaptable cellular organelles are to various constant mechanical stresses. (a, b) Shows mitochondria in adipocytes. The right side of homogeneous light gray content represents the lipid droplet. (c) Shows a few mitochondria in proximity to the cell nucleus. (d, e) Shows the shape of the cell nucleus in different mechanical constraints induced by the size of the lipid droplets. Again, the homogeneous light gray content represents the lipid droplets from the surrounding cells. (f) Shows two adipocytes with adjacent nuclei. Within each nucleus (c–f), the genetic material can be observed in different states of activity. Inside each nucleus, the dark gray (to almost black) areas represent heterochromatin and the normal gray areas represent euchromatin. In short, euchromatin contains a specific and dynamic set of active genes that is expressed only in adipocytes, while areas of heterochromatin contain the remaining unexpressed genes. At the edge of the nuclear membrane, nuclear pores can be observed. Interruptions with a light gray hue can be seen along the perimeter of the nuclear membrane. Those are the nuclear pores. Note that each image shows only a small fraction of the actual size of an adipocyte.

Source: Courtesy Dr. Elvira Gagniuc, Department of Pathology, Faculty of Veterinary Medicine, University of Agronomic Sciences and Veterinary Medicine, Bucharest.

Nevertheless, chromatin also undergoes partial changes while in G0 phase (the resting stage of the cell cycle – e.g. many neuronal cells are always in this state). These partial and continuous changes of the chromatin structure are meant to silence or activate certain genes from the main subset of genes. Such facultative heterochromatin areas are present on the outer surface of the heterochromatin landscape (the euchromatin – heterochromatin borders), and their condensation state depends on successive interactions between different gene products of the subset [31]. Note that DNA molecules are present not only in the area of the cell nucleus but also in other organelles (e.g. mitochondria and chloroplasts). Much like in prokaryotes, the circular double-stranded DNA molecules found in these eukaryotic organelles show their own type of organization called a nucleoid (meaning nucleus-like; it is an infrequent DNA–protein assembly) [38, 39].

Figure 1.3 Molecular representations. (a) Shows the structure of the nucleosome core particle [52, 53]. (b) Shows the path of mRNA through the ribosome by pointing out the collinearity between the tRNA anticodons [53, 54]. The window highlights the binding region between an amino acid and a tRNA. (c) Shows the Escherichia coli glutaminyl transfer RNA synthetase complexed with transfer RNA(Gln) and ATP [53, 55]. The tRNA sequence is presented next to this ribonucleoprotein particle. The last letters in the sequence correspond in reverse order to the region in the tRNA highlighted by the dotted line window (i.e. “ACCG …”). The position of the tRNA anticodon is also highlighted here.

Source: Refs. [52, 53, 55].