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Chromatin 3D – will it make understanding of cancer transformation finally possible?

Chromatin 3D – will it make understanding of cancer transformation finally possible? Cancer – releasing the cell from its subordination to the organismModern developments in genetics have provided us with in-depth knowledge of numerous pathological processes, including neoplastic transformation; however, despite enormous progress in the area, the phenomenon itself remains insufficiently understood. Histopathologists locate tumors by looking for cells that do not conform to the characteristic layout expected in a given tissue. Examples include local uncontrolled hyperplasia of epithelial cells and/or polymorphic tissue cells, often with large hyperchromic nuclei, indicative of significant genomic alterations (Figure 1). In general, this phenomenon shows that the cells in question do not follow orders issued by the organism. An unusual property of cancer cells is their capacity for rapid proliferation – despite being saddled with numerous mutations, which typically accompany carcinogenesis [1], [2], [3]. Rather than becoming deficient and quiescent, such cells are often capable of vigorous activity. It can be concluded that, as a result of genetic transformation, cells become free from the constraints imposed by their host organism and gain autonomy similar to that of their single-cell evolutionary antecedent [4], [5]. This conclusion is borne out by historical evidence. In the course of evolution, eukaryotic cells appeared some 1.6 billion years ago, while complex organisms evolved much later – approximately during the Cambrian period (543–490 million years ago). This development marked an evolutionary milestone since cells, which had hitherto acted as free units, became dependent on the needs and requirements of their parent organisms. The basic properties that express this hierarchical subordination of free cells are as follows:Figure 1:Osteosarcoma – polymorphic tumor cells.capability for differentiation and conformance with epigenetic principles;controlled senescence and apoptosis (through the action of telomerase which prevents functional immortality), with certain types of cells subject to mechanical elimination (e.g. exfoliation and abrasion);a shift toward more efficient oxygen economy (water synthesis);capability for division governed by “stop” signals produced by neighboring cells (so-called contact inhibition, enabling creation of functional tissues) [6], [7], [8], [9], [10], [11], [12], [13].The formation of organisms, despite being regarded as a pivotal moment in evolutionary development, still lacks a sound genetic explanation. Consequently, the relation between genes that drove this process and those that often undergo mutations in the course of carcinogenesis remains unclear. Comparative analysis of tumor cell genomes, made possible by extraordinary progress in DNA-sequencing techniques, reveals some common mutations, frequently observed in neoplastic tissue [14], [15], [16], [17], [18], [19]. The implicated genes are sometimes called “drivers”, while other genes where mutations are consistent with a statistical distribution are referred to as “passengers”. The “drivers” in particular are thought to hold the key to understanding cancer transformation [20]. In this context, arguably the most frequently occurring mutation is that of TP53, evident in over 50% of neoplasms [21]. Common mutations also affect WHL, FLT3, APC, ARIDIA, PIK3CA, NPN1, CRAS, FBXW7, MLL, KDM6A, and other certain genes [15], [16].Interestingly, most of the commonly listed genes mediate communication between the organism and its constituent cells, specifically by suppressing signals. Other groups that commonly undergo mutations include genes responsible for DNA maintenance and repair as well as for epigenetic effects and structuralization of chromatin [5], [22].Spatial structure of chromatin as seen todayDespite having identified mutations that promote cancer transformation, the exact mechanism of tumorigenesis remains unclear. Notably, the presented mutations do not provide a direct link between the function of the afflicted genes and characteristic properties of neoplastic tissue, such as deficient contact inhibition and other aberrations related to organism/cell interaction. Nevertheless, recent years have seen an explosion in genetic research, raising hopes for in-depth understanding of tumorigenesis. Interesting new developments include focus on the spatial (three-dimensional, 3D) structure of chromatin, which in itself carries information and may explain certain pathologies. This structure determines the properties of DNA, both in the nucleus during interphase and in the chromosomes during cell division [23], [24], [25], [26].The 3D structure of chromatin comprises independent loops of DNA that fold to form globular structures, much like polypeptides. In the human genome, the average length of a loop is on the order of 1 Mb, with nearly 2000 loops in total, comprising 90% of the genome [27]. Each loop houses approximately 8–12 genes in addition to crucial enhancer sequences. It is thought that these loops act as independent units and that each facilitates a specific biological function. Looping and folding of DNA permits enhancer sequences to contact their target genes, despite significant separation. Such loops, called topologically associated domains (TADs), likely arose during the same period in evolution as the first complex organisms.The presented structural arrangement of DNA is somewhat consistent with theoretical expectations. Gene expression depends on the action of enhancers, which is usually nonspecific as involving activation of the same enzyme – RNA polymerase. Under these conditions, specificity may only be attained by isolating genes responsible for a given function and by pairing them with the required enhancers. Of course, such enhancers must be activated by external signals – transcription factors and hormonal receptors (e.g. steroid hormones). TADs are separated from one another by free DNA fragments. This mutual isolation minimizes undesirable contacts and prevents enhancers from acting upon adjacent loops. It also facilitates efficient packing of chromatin [28], [29], [30] (Figure 2).Figure 2:Basic components of the 3D structure of chromatin.(A) Model TAD, showing the CTCF and cohesin locations as well as a sample enhancer and its target gene. (B) Alternative structural variant of a TAD. (C) Complex TAD produced by folded DNA. (D) Sequence of TADs separated by isolating DNA fragments. (E) topologically associated chromosomal domain (TACD) comprising several TADs and enabling interactions between distant sequences.The formation of TADs is spontaneous but precise. It depends on information contained in DNA itself – more specifically, on the presence of special sequences that are recognized by transcription factors known as CTCF. The actual task of forming a TAD, however, falls to a protein complex known as cohesin, powered by ATP. This protein attaches to DNA and initiates creation of a loop until it comes into contact with CTCF, which inhibits its ATPase activity, thus limiting the size of the loop. Ultimately, cohesin forms a complex with several other proteins (including CTCF) and latches at the base of the loop, stabilizing the TAD [31], [32] (Figure 3).Figure 3:Hypothetical TAD formation mechanism.(A) Model view of cohesin, which creates a TAD. (B) Resulting TAD.This mechanism effectively partitions DNA into functional segments.An independent division into heterochromatic and euchromatic genomic compartments exists and relies on epigenetic factors, including methylation of histones (H3K27me3) and of DNA itself [33], [34], [35].The controlled 3D structure of chromatin not only enables important biological processes, but also introduces dangers related to strong dependence on the spatial arrangement of matter. For example, the required contact between promoters and enhancers is an extremely sensitive mechanism that is easy to disrupt, e.g. when the size of the loop changes due to duplications or deletions [36], [37], [38]. Even more frequent are anomalies during the TAD formation process (note that TADs must be recreated following each cell division). In this context, mutations in sequences recognized by CTCF transcription factors are regarded as especially dangerous since they lead to misalignment between genes and enhancers, possibly spilling over to adjacent loops and disrupting their function as well. This observation provides fresh insight into the cancer transformation process, since research to date tended to focus on individual mutations, particularly those frequently observed in various cancers (so-called drivers). The underlying hope was that analysis of such mutations would lead to a discovery of a common process or property shared by all cancers and therefore the generic cause of cancer transformation. In a model approach, mutations can be compared to damage sustained by a building. While some problems are benign and easily tolerated, serious ones – such as cracked walls – have far-reaching consequences and may even cause conflicts between neighbors. Similar effects are observed in the genome when mutations disrupt proper structuralization of chromatin (i.e. by disabling CTCF factors or other mechanisms involved in this process) [39], [40]. As a result of such mutations, enhancers become misaligned with their target genes, which, in turn, leads to activation of improper genes or inhibition of genes that need to be expressed. Disruption of the 3D chromatin structure may also cause domains to fuse or become fragmented (Figure 4). All these effects negatively affect the delicate spatial balance that the cell relies on to fulfill its role in the organism. While the underlying mutation remains localized, its effects may spread to distant portions of the genome and effectively prevent the cell from functioning. Such changes are also sometimes evident in the structure of chromosomes [41]. When they encroach upon vital cellular machinery, the cell may become neoplastic.Figure 4:Aberrations in the 3D structure of chromatin.(A) Simple TAD formed by looped DNA. (B) Result of mutations affecting CTCF transcription factors and disrupting the function of adjacent loops (see Figure 2E). Enhancer/gene misalignment (broken contacts or new undesirable points of contact). Yellow dot: target gene; black dot: enhancer.Conclusions and future outlookNegation of the cell/organism command hierarchy cannot be fully explained by point mutations alone, even when such mutations promote cancer transformation in vivo, e.g. by predisposing the cell to unrestricted divisions. The mechanism of transformation must involve many genes, including those engaged in tissue formation. Destabilization of the spatial structure of chromatin may result in a “genomic earthquake” which meets this requirement. Although a comprehensive formal description of the presented phenomenon has not yet been proposed, modern IT tools that enable the biologists to study the 3D structure of chromatin seem a promising development in the search for the causes of cancer.Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.Research funding: None declared.Employment or leadership: None declared.Honorarium: None declared.Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.References[1]Porta-Pardo E, Kamburov A, Tamborero D, Pons T, Grases D, Valencia A, et al. Comparison of algorithms for the detection of cancer drivers at subgene resolution. 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Essential medical genetics. Oxford: Blackwell Science, 1997.Ferguson-SmithMEssential medical geneticsOxfordBlackwell Science1997 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bio-Algorithms and Med-Systems de Gruyter

Chromatin 3D – will it make understanding of cancer transformation finally possible?

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de Gruyter
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©2018 Walter de Gruyter GmbH, Berlin/Boston
ISSN
1896-530X
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1896-530X
DOI
10.1515/bams-2018-0002
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Abstract

Cancer – releasing the cell from its subordination to the organismModern developments in genetics have provided us with in-depth knowledge of numerous pathological processes, including neoplastic transformation; however, despite enormous progress in the area, the phenomenon itself remains insufficiently understood. Histopathologists locate tumors by looking for cells that do not conform to the characteristic layout expected in a given tissue. Examples include local uncontrolled hyperplasia of epithelial cells and/or polymorphic tissue cells, often with large hyperchromic nuclei, indicative of significant genomic alterations (Figure 1). In general, this phenomenon shows that the cells in question do not follow orders issued by the organism. An unusual property of cancer cells is their capacity for rapid proliferation – despite being saddled with numerous mutations, which typically accompany carcinogenesis [1], [2], [3]. Rather than becoming deficient and quiescent, such cells are often capable of vigorous activity. It can be concluded that, as a result of genetic transformation, cells become free from the constraints imposed by their host organism and gain autonomy similar to that of their single-cell evolutionary antecedent [4], [5]. This conclusion is borne out by historical evidence. In the course of evolution, eukaryotic cells appeared some 1.6 billion years ago, while complex organisms evolved much later – approximately during the Cambrian period (543–490 million years ago). This development marked an evolutionary milestone since cells, which had hitherto acted as free units, became dependent on the needs and requirements of their parent organisms. The basic properties that express this hierarchical subordination of free cells are as follows:Figure 1:Osteosarcoma – polymorphic tumor cells.capability for differentiation and conformance with epigenetic principles;controlled senescence and apoptosis (through the action of telomerase which prevents functional immortality), with certain types of cells subject to mechanical elimination (e.g. exfoliation and abrasion);a shift toward more efficient oxygen economy (water synthesis);capability for division governed by “stop” signals produced by neighboring cells (so-called contact inhibition, enabling creation of functional tissues) [6], [7], [8], [9], [10], [11], [12], [13].The formation of organisms, despite being regarded as a pivotal moment in evolutionary development, still lacks a sound genetic explanation. Consequently, the relation between genes that drove this process and those that often undergo mutations in the course of carcinogenesis remains unclear. Comparative analysis of tumor cell genomes, made possible by extraordinary progress in DNA-sequencing techniques, reveals some common mutations, frequently observed in neoplastic tissue [14], [15], [16], [17], [18], [19]. The implicated genes are sometimes called “drivers”, while other genes where mutations are consistent with a statistical distribution are referred to as “passengers”. The “drivers” in particular are thought to hold the key to understanding cancer transformation [20]. In this context, arguably the most frequently occurring mutation is that of TP53, evident in over 50% of neoplasms [21]. Common mutations also affect WHL, FLT3, APC, ARIDIA, PIK3CA, NPN1, CRAS, FBXW7, MLL, KDM6A, and other certain genes [15], [16].Interestingly, most of the commonly listed genes mediate communication between the organism and its constituent cells, specifically by suppressing signals. Other groups that commonly undergo mutations include genes responsible for DNA maintenance and repair as well as for epigenetic effects and structuralization of chromatin [5], [22].Spatial structure of chromatin as seen todayDespite having identified mutations that promote cancer transformation, the exact mechanism of tumorigenesis remains unclear. Notably, the presented mutations do not provide a direct link between the function of the afflicted genes and characteristic properties of neoplastic tissue, such as deficient contact inhibition and other aberrations related to organism/cell interaction. Nevertheless, recent years have seen an explosion in genetic research, raising hopes for in-depth understanding of tumorigenesis. Interesting new developments include focus on the spatial (three-dimensional, 3D) structure of chromatin, which in itself carries information and may explain certain pathologies. This structure determines the properties of DNA, both in the nucleus during interphase and in the chromosomes during cell division [23], [24], [25], [26].The 3D structure of chromatin comprises independent loops of DNA that fold to form globular structures, much like polypeptides. In the human genome, the average length of a loop is on the order of 1 Mb, with nearly 2000 loops in total, comprising 90% of the genome [27]. Each loop houses approximately 8–12 genes in addition to crucial enhancer sequences. It is thought that these loops act as independent units and that each facilitates a specific biological function. Looping and folding of DNA permits enhancer sequences to contact their target genes, despite significant separation. Such loops, called topologically associated domains (TADs), likely arose during the same period in evolution as the first complex organisms.The presented structural arrangement of DNA is somewhat consistent with theoretical expectations. Gene expression depends on the action of enhancers, which is usually nonspecific as involving activation of the same enzyme – RNA polymerase. Under these conditions, specificity may only be attained by isolating genes responsible for a given function and by pairing them with the required enhancers. Of course, such enhancers must be activated by external signals – transcription factors and hormonal receptors (e.g. steroid hormones). TADs are separated from one another by free DNA fragments. This mutual isolation minimizes undesirable contacts and prevents enhancers from acting upon adjacent loops. It also facilitates efficient packing of chromatin [28], [29], [30] (Figure 2).Figure 2:Basic components of the 3D structure of chromatin.(A) Model TAD, showing the CTCF and cohesin locations as well as a sample enhancer and its target gene. (B) Alternative structural variant of a TAD. (C) Complex TAD produced by folded DNA. (D) Sequence of TADs separated by isolating DNA fragments. (E) topologically associated chromosomal domain (TACD) comprising several TADs and enabling interactions between distant sequences.The formation of TADs is spontaneous but precise. It depends on information contained in DNA itself – more specifically, on the presence of special sequences that are recognized by transcription factors known as CTCF. The actual task of forming a TAD, however, falls to a protein complex known as cohesin, powered by ATP. This protein attaches to DNA and initiates creation of a loop until it comes into contact with CTCF, which inhibits its ATPase activity, thus limiting the size of the loop. Ultimately, cohesin forms a complex with several other proteins (including CTCF) and latches at the base of the loop, stabilizing the TAD [31], [32] (Figure 3).Figure 3:Hypothetical TAD formation mechanism.(A) Model view of cohesin, which creates a TAD. (B) Resulting TAD.This mechanism effectively partitions DNA into functional segments.An independent division into heterochromatic and euchromatic genomic compartments exists and relies on epigenetic factors, including methylation of histones (H3K27me3) and of DNA itself [33], [34], [35].The controlled 3D structure of chromatin not only enables important biological processes, but also introduces dangers related to strong dependence on the spatial arrangement of matter. For example, the required contact between promoters and enhancers is an extremely sensitive mechanism that is easy to disrupt, e.g. when the size of the loop changes due to duplications or deletions [36], [37], [38]. Even more frequent are anomalies during the TAD formation process (note that TADs must be recreated following each cell division). In this context, mutations in sequences recognized by CTCF transcription factors are regarded as especially dangerous since they lead to misalignment between genes and enhancers, possibly spilling over to adjacent loops and disrupting their function as well. This observation provides fresh insight into the cancer transformation process, since research to date tended to focus on individual mutations, particularly those frequently observed in various cancers (so-called drivers). The underlying hope was that analysis of such mutations would lead to a discovery of a common process or property shared by all cancers and therefore the generic cause of cancer transformation. In a model approach, mutations can be compared to damage sustained by a building. While some problems are benign and easily tolerated, serious ones – such as cracked walls – have far-reaching consequences and may even cause conflicts between neighbors. Similar effects are observed in the genome when mutations disrupt proper structuralization of chromatin (i.e. by disabling CTCF factors or other mechanisms involved in this process) [39], [40]. As a result of such mutations, enhancers become misaligned with their target genes, which, in turn, leads to activation of improper genes or inhibition of genes that need to be expressed. Disruption of the 3D chromatin structure may also cause domains to fuse or become fragmented (Figure 4). All these effects negatively affect the delicate spatial balance that the cell relies on to fulfill its role in the organism. While the underlying mutation remains localized, its effects may spread to distant portions of the genome and effectively prevent the cell from functioning. Such changes are also sometimes evident in the structure of chromosomes [41]. When they encroach upon vital cellular machinery, the cell may become neoplastic.Figure 4:Aberrations in the 3D structure of chromatin.(A) Simple TAD formed by looped DNA. (B) Result of mutations affecting CTCF transcription factors and disrupting the function of adjacent loops (see Figure 2E). Enhancer/gene misalignment (broken contacts or new undesirable points of contact). Yellow dot: target gene; black dot: enhancer.Conclusions and future outlookNegation of the cell/organism command hierarchy cannot be fully explained by point mutations alone, even when such mutations promote cancer transformation in vivo, e.g. by predisposing the cell to unrestricted divisions. The mechanism of transformation must involve many genes, including those engaged in tissue formation. Destabilization of the spatial structure of chromatin may result in a “genomic earthquake” which meets this requirement. Although a comprehensive formal description of the presented phenomenon has not yet been proposed, modern IT tools that enable the biologists to study the 3D structure of chromatin seem a promising development in the search for the causes of cancer.Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.Research funding: None declared.Employment or leadership: None declared.Honorarium: None declared.Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.References[1]Porta-Pardo E, Kamburov A, Tamborero D, Pons T, Grases D, Valencia A, et al. Comparison of algorithms for the detection of cancer drivers at subgene resolution. 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Journal

Bio-Algorithms and Med-Systemsde Gruyter

Published: Mar 30, 2018

References