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Centromere Chromatin Shows How Histone Variants Create Special Structures

Nucleosomes that contain histone variants have their own unique characteristics and are thought to be capable of leaving chromatin markings that are unusually stable over time. When a cell divides, an important illustration is the development and transmission of the specialized chromatin structure at the centromere. The centromere is the region of each chromosome that is required for attachment to the mitotic spindle and the orderly segregation of the duplicated copies of the genome into daughter cells. This structure is passed down from parent to child during cell division. Even though the attachment of the centromere to the spindle and movement of the DNA only take place during mitosis, each centromere in many complex species, including humans, is encased in a section of unique centromeric chromatin that persists during interphase. This is the case despite the fact that mitosis is the only phase in which mitosis takes place. In addition to other proteins that pack the nucleosomes into unusually dense configurations and produce the kinetochore, which is the one-of-a-kind structure that is required for the attachment of the mitotic spindle, this chromatin contains a centromere-specific variant of H3 histone that is known as CENP-A.


One particular DNA sequence containing around 125 nucleotide pairs has the potential to function as a centromere in the yeast S. cerevisiae. This DNA sequence contains around a dozen unique proteins, one of which is a variant of histone H3 called CENP-A. This variant, along with the three other core histones, creates a nucleosome that is specific to centromeres. At the yeast centromere, additional proteins link a single microtubule from the mitotic spindle to this nucleosome. This connection is made at the yeast centromere.


The centromeres of more complex organisms are noticeably larger in size when compared to those of budding yeasts. For example, despite the fact that fly and human centromeres contain CENP-A, it does not appear that they have a DNA sequence that is unique to centromeres. Instead, they are composed of tens of millions of individual nucleotide pairs. In human beings, the majority of these centromeres are composed of brief DNA sequences that repeat themselves. This type of DNA is known as alpha satellite DNA. However, due to the fact that identical repetitive sequences are also found in other places on chromosomes that are not centromeric, it is clear that they are not sufficient to control the formation of centromeres, as shown by the fact that they are present there. Neocentromeres, which are also known as brand-new human centromeres, have been seen to spontaneously arise on broken-down chromosomes on extremely rare occasions. This is perhaps the most significant finding. Some of these unique locations were initially euchromatic and are completely devoid of any alpha satellite DNA. It would appear that the definition of centromeres in complex organisms is not determined by a particular DNA sequence but rather by an assembly of proteins.

It would appear that the origination of some centromeres through de novo processes and the inactivation of other centromeres played a significant part in the process of evolution. It is common for different species to have a different number of chromosomes, even when they are very closely related to one another. In-depth comparisons of genomes have shown that numerous instances of chromosome breakage and rejoining processes have resulted in the creation of unique chromosomes. Some of these chromosomes must have initially included abnormal numbers of centromeres, either more than one or none at all. We will go into more detail about these findings in the following section. However, for stable inheritance, each chromosome needs to have one and only one centromere. Only then can inheritance be considered stable. It seems that extra centromeres needed to be deactivated or replaced with new ones in order to ensure the stability of the altered chromosome sets. This was done in one of two ways.

It has been hypothesized that the initial seeding event for the production of de novo centromeres involves the development of a certain DNA-protein complex that contains nucleosomes synthesized with the histone H3 CENP-A variant. This theory has been put forward as a working hypothesis. This seeding event happens more frequently on arrays of alpha satellite DNA in humans than it does on other DNA sequences. At a replication fork, the H3-H4 tetramers are directly inherited by the sister DNA helices from each nucleosome on the paternal DNA helix by the sister DNA helices. Once a collection of CENP-A-containing nucleosomes has been created on a stretch of DNA, it is therefore simple to appreciate how a new centromere can be produced in the same spot on both daughter chromosomes after each cycle of cell division. It is sufficient to postulate that the CENP-A histone, when it is present in an inherited nucleosome, selectively attracts additional CENP-A histone to its newly formed neighbors in order to understand this phenomenon.

There are a number of notable parallels between the development and maintenance of heterochromatin-containing sites like centromeres and other parts of the genome that contain heterochromatin. It is believed that the formation of centromeric chromatin is a highly cooperative process that radiates out from an initial seed in a manner that is comparable to the phenomena of position effect variegation that we previously investigated. This is because it is thought that centromeric chromatin is formed in the same way that position effect variegation occurs. To be more specific, the formation of the full centromere occurs as an all-or-none entity. Following each cycle of chromosome replication, a certain chromatin structure seems to be directly inherited in each case. This is the case regardless of the situation. Therefore, not only can a cooperative recruitment of proteins and the activity of reader-writer complexes explain how certain chromatin forms spread along the chromosome in space, but they can also explain how chromatin spreads from parent cell to daughter cell. This is because reader-writer complexes are responsible for reading and writing chromatin.

The development of multicellular organisms is dependent on a system of inheritance that is controlled by epigenetic factors. Their differentiated cell types are established during development, and they continue to do so even after undergoing a large number of cell division cycles. During development. In spite of the fact that they inherit the same genome, the daughters of a liver cell continue to function as liver cells, while the daughters of an epidermal cell continue to function as epidermal cells, and so on. This occurs as a result of the faithful transmission of individual patterns of gene expression from the parent cell to the daughter cell. The structure of the chromatin is involved in this process of epigenetic information transmission from one cell generation to the next.

One line of evidence supporting this theory comes from experiments in which the nucleus of a frog or tadpole cell is transferred into an egg from which the original nucleus has been removed (an enucleated egg). It was shown in a series of studies that were conducted in 1968 that the differentiated nucleus of a donor cell could be reprogrammed in such a way as to allow for the development of an entirely new tadpole. These experiments are considered to be among the most important in the field. However, this reprogramming is difficult to do and its efficacy decreases steadily when older animal nuclei are used in the experiment. For instance, only 2% of enucleated eggs that were given a donor nucleus extracted from a tadpole epithelial cell reached the swimming tadpole stage, whereas 35% of enucleated eggs reached this stage when the donor nuclei were taken from an early (gastrula-stage) embryo. This difference in success rate was due to the fact that the donor nuclei came from a tadpole epithelial cell rather than an Using cutting-edge experimental methods, it is now possible to determine the source of this reprogramming-resistant behavior. It arises, at least in part, as a consequence of the fact that specific chromatin structures in the initial differentiated nucleus have a tendency to persist and be passed on over the course of the numerous cell-division cycles that are required for embryonic development. These structures play an essential role in the development of the embryo. It has been demonstrated in tests conducted on Xenopus embryos that some types of active or repressive chromatin structures can persist for up to 24 cell divisions, which results in the aberrant expression of genes. Figure 4-45 provides a condensed summary of one experiment that was conducted along these lines and focused on chromatin bearing the histone variant H3.3.


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Centromere Chromatin Shows How Histone Variants Create Special Structures

Nucleosomes that contain histone variants have their own unique characteristics and are thought to be capable of leaving chromatin markings that are unusually stable over time. When a cell divides, an important illustration is the development and transmission of the specialized chromatin structure at the centromere. The centromere is the region of each chromosome that is required for attachment to the mitotic spindle and the orderly segregation of the duplicated copies of the genome into daughter cells. This structure is passed down from parent to child during cell division. Even though the attachment of the centromere to the spindle and movement of the DNA only take place during mitosis, each centromere in many complex species, including humans, is encased in a section of unique centromeric chromatin that persists during interphase. This is the case despite the fact that mitosis is the only phase in which mitosis takes place. In addition to other proteins that pack the nucleosomes into unusually dense configurations and produce the kinetochore, which is the one-of-a-kind structure that is required for the attachment of the mitotic spindle, this chromatin contains a centromere-specific variant of H3 histone that is known as CENP-A.


One particular DNA sequence containing around 125 nucleotide pairs has the potential to function as a centromere in the yeast S. cerevisiae. This DNA sequence contains around a dozen unique proteins, one of which is a variant of histone H3 called CENP-A. This variant, along with the three other core histones, creates a nucleosome that is specific to centromeres. At the yeast centromere, additional proteins link a single microtubule from the mitotic spindle to this nucleosome. This connection is made at the yeast centromere.


The centromeres of more complex organisms are noticeably larger in size when compared to those of budding yeasts. For example, despite the fact that fly and human centromeres contain CENP-A, it does not appear that they have a DNA sequence that is unique to centromeres. Instead, they are composed of tens of millions of individual nucleotide pairs. In human beings, the majority of these centromeres are composed of brief DNA sequences that repeat themselves. This type of DNA is known as alpha satellite DNA. However, due to the fact that identical repetitive sequences are also found in other places on chromosomes that are not centromeric, it is clear that they are not sufficient to control the formation of centromeres, as shown by the fact that they are present there. Neocentromeres, which are also known as brand-new human centromeres, have been seen to spontaneously arise on broken-down chromosomes on extremely rare occasions. This is perhaps the most significant finding. Some of these unique locations were initially euchromatic and are completely devoid of any alpha satellite DNA. It would appear that the definition of centromeres in complex organisms is not determined by a particular DNA sequence but rather by an assembly of proteins.

It would appear that the origination of some centromeres through de novo processes and the inactivation of other centromeres played a significant part in the process of evolution. It is common for different species to have a different number of chromosomes, even when they are very closely related to one another. In-depth comparisons of genomes have shown that numerous instances of chromosome breakage and rejoining processes have resulted in the creation of unique chromosomes. Some of these chromosomes must have initially included abnormal numbers of centromeres, either more than one or none at all. We will go into more detail about these findings in the following section. However, for stable inheritance, each chromosome needs to have one and only one centromere. Only then can inheritance be considered stable. It seems that extra centromeres needed to be deactivated or replaced with new ones in order to ensure the stability of the altered chromosome sets. This was done in one of two ways.

It has been hypothesized that the initial seeding event for the production of de novo centromeres involves the development of a certain DNA-protein complex that contains nucleosomes synthesized with the histone H3 CENP-A variant. This theory has been put forward as a working hypothesis. This seeding event happens more frequently on arrays of alpha satellite DNA in humans than it does on other DNA sequences. At a replication fork, the H3-H4 tetramers are directly inherited by the sister DNA helices from each nucleosome on the paternal DNA helix by the sister DNA helices. Once a collection of CENP-A-containing nucleosomes has been created on a stretch of DNA, it is therefore simple to appreciate how a new centromere can be produced in the same spot on both daughter chromosomes after each cycle of cell division. It is sufficient to postulate that the CENP-A histone, when it is present in an inherited nucleosome, selectively attracts additional CENP-A histone to its newly formed neighbors in order to understand this phenomenon.

There are a number of notable parallels between the development and maintenance of heterochromatin-containing sites like centromeres and other parts of the genome that contain heterochromatin. It is believed that the formation of centromeric chromatin is a highly cooperative process that radiates out from an initial seed in a manner that is comparable to the phenomena of position effect variegation that we previously investigated. This is because it is thought that centromeric chromatin is formed in the same way that position effect variegation occurs. To be more specific, the formation of the full centromere occurs as an all-or-none entity. Following each cycle of chromosome replication, a certain chromatin structure seems to be directly inherited in each case. This is the case regardless of the situation. Therefore, not only can a cooperative recruitment of proteins and the activity of reader-writer complexes explain how certain chromatin forms spread along the chromosome in space, but they can also explain how chromatin spreads from parent cell to daughter cell. This is because reader-writer complexes are responsible for reading and writing chromatin.

The development of multicellular organisms is dependent on a system of inheritance that is controlled by epigenetic factors. Their differentiated cell types are established during development, and they continue to do so even after undergoing a large number of cell division cycles. During development. In spite of the fact that they inherit the same genome, the daughters of a liver cell continue to function as liver cells, while the daughters of an epidermal cell continue to function as epidermal cells, and so on. This occurs as a result of the faithful transmission of individual patterns of gene expression from the parent cell to the daughter cell. The structure of the chromatin is involved in this process of epigenetic information transmission from one cell generation to the next.

One line of evidence supporting this theory comes from experiments in which the nucleus of a frog or tadpole cell is transferred into an egg from which the original nucleus has been removed (an enucleated egg). It was shown in a series of studies that were conducted in 1968 that the differentiated nucleus of a donor cell could be reprogrammed in such a way as to allow for the development of an entirely new tadpole. These experiments are considered to be among the most important in the field. However, this reprogramming is difficult to do and its efficacy decreases steadily when older animal nuclei are used in the experiment. For instance, only 2% of enucleated eggs that were given a donor nucleus extracted from a tadpole epithelial cell reached the swimming tadpole stage, whereas 35% of enucleated eggs reached this stage when the donor nuclei were taken from an early (gastrula-stage) embryo. This difference in success rate was due to the fact that the donor nuclei came from a tadpole epithelial cell rather than an Using cutting-edge experimental methods, it is now possible to determine the source of this reprogramming-resistant behavior. It arises, at least in part, as a consequence of the fact that specific chromatin structures in the initial differentiated nucleus have a tendency to persist and be passed on over the course of the numerous cell-division cycles that are required for embryonic development. These structures play an essential role in the development of the embryo. It has been demonstrated in tests conducted on Xenopus embryos that some types of active or repressive chromatin structures can persist for up to 24 cell divisions, which results in the aberrant expression of genes. Figure 4-45 provides a condensed summary of one experiment that was conducted along these lines and focused on chromatin bearing the histone variant H3.3.


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