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A structure is the basis of genetic function. The information content of resides in the sequence of its bases in DNA. Although DNA has only four different nitrogenous bases, the potential for different arrangements, and thus, a wide sets of genes in a nucleotide is astounding. In the process of DNA replication, the double helix unwinds exposing the bases in each strand of DNA. They function as templates for the synthesis of a second complementary strand. Resulting, in the formation of a newly synthesized that is complementary to the parent strand. For instance, an adenine at one position signals the addition of a thymine at the position on the newly forming strand. Similarly, A calls for T, G calls for C, and C calls for G. Once all the bases are correctly orientated, enzymes bind the nucleotides with one another and creating a continuous strand. This phenomenon of complement base pairing followed by the coupling of nucleotides create two double helixes that contain one of the parent DNA strand, and a completely new strand. Such a pattern of double helix duplication is called semi conservative replication: a copying in which one strand is conserved from the parent molecule and the other is newly synthesized. In Figure 1, depicts a model of DNA replication with the end result of two identical double helixes. Enzymes and transcriptional factors are required to initiate DNA replication. Proteins bind to the origin of replication forming a stable configuration of exposed bases. The actual formation of new DNA is done by DNA polymerase III, adding nucleotides, one after another. It functions only in the 5' to 3'direction and catalyzes the joining of paired nucleotide to the 3'end of the growing chain. As DNA replication continues, helicase progressively unwinds the DNA, allowing DNA polymerase III to move in the same direction to synthesize the new chain under construction. The enzyme adds nucleotides continuously to the growing 3' end as soon as helicase exposes the bases on the template strand. It encounters no problems in the polymerization of the chain; this chain is known as the leading strand. On the other hand, problems are present for the complement base pairing on the second DNA strand, the lagging strand. Consequently, the lagging strand is synthesized discontinuously into small fragments called Okazaki fragment. DNA polymerase still synthesizes the small fragments in the 5' to 3' direction. But each Okazaki fragment is initiated by the synthesis of short RNA primer. Finallly, DNA polymerase II and other enzymes remove the RNA primer on the fragments, and DNA ligase covalently joins the Okazaki fragments into a continuous strand of DNA. When both leading and lagging strands are established, DNA replication is complete. semiconservative.gif
Changes in DNA structure are caused by transcription factor proteins. Cis-acting elements at a gene are sequences that serve as attachment sites for the DNA -binding proteins and micro-RNAs that regulate the initiation of transcription. For example, the promoter is a cis-acting element that is very close to the gene's initiation site. The attachment of RNA polymerase allows the first step in transcription. Also, enhancers are another class of cis-acting elements that have the ability to retain original function even when moved far from the gene whose transcription they influence; their binding of proteins activates or represses transcription. The enhancer regions of some genes are very large, some containing multiple elements that make it possible to fine-tune control the regulation of a gene (maybe cite). This is particularly important for gene expression in multicellular organisms that must be expressed in many different tissues. The string gene in Drosophila is an example. The gene encodes a protein that activates the fourteenth mitosis of embryonic development. (cite with differ soucre) Trans-acting elements are genes located elsewhere in the genome. They encode proteins or micro-RNAs that interact directly or indirectly with its target gene's cis-acting elemtss to activate or repress expression of the target gene. Trans-acting proteins and RNAs that regulate transcription are known as transcription factors. Basal factors facilitate binding of RNA polymerase and initiate low levels of gene expression. Activators are transcriptional factors that bind to different enhancer elements. They can interact directly or indirectly with basal factors to cause an increase in transcriptional factors. (Cite from a different book) The enormous range of transcriptional regulation occurs through the binding of these transcriptional and basal factors to enhancers and promoters that are associated with different genes. This allows a cell to transcribe different genes into a widely amount of mRNA. Many transcriptional factors are multimeric proteins composed of identical or nonidentical subunits. One of the most common is the leucine zipper motif, an amino acid sequence the twirls into an Î± helix with leucine residues protruding at regular intervals (cite the cell book). The ability to form heterdimers greatly increases the number of gene products. The specificity of transcription factors can be altered by other molecules in the cell. One example of this is observed with the yeast Î±2 repressor, which helps determine the mating type of a cell. Yeast cells can be either haploid or diploid, and haploid cells come in two mating types: Î± and a. In Î± cells, the Î±2 repressor binds to enhancers that control the activity of a set of a-determining genes, whose expression would make the cell type a cells. In the diploid cells, the Î±2 repressor plays a different role. It maintains the diploid state by repressing the haploid-specific genes (cite the cell book). Transcriptional factors are not fixated into one function. Furthermore, regulatory regions contain multiple enhancers, each with the ability to bind different activators and repressors. Throughout development, dozens of transcriptional factors whose affinities for DNA, are modulated by binding to other molecules. Changes in the cell's environment, dispatch signal molecules to bind to receptors in the cell's plasma membrane that cause changes in the balance of transcription factors or their relative affinities for DNA. The biochemical integration of these mechanism mention yields a precise level of transcription activation or repression.
Chromatin is a tightly intertwined compaction of DNA and proteins interacting forming its intrinsically linear structural configuration. Chromatin proteins are traditionally classified into two general groups: Histones and nonhistone chromosomal proteins. DNA wraps around histone cores to from the chromatin fiber, observed as a beads-on-a-structure. Each bead is a nucleosome the contains DNA wrapped around a core composed of eight histone- two each of H2A, H2B, H3, and H4. An addition, linker DNA connects one nucleosome with the next. Histones are responsible to maintain the shape and structure of chromatin. As shown in Figure 2, the nucleosome structure reveals how DNA is packaged. The negatively charge nature of DNA attract with the positively charged histone proteins. The spacing and structure of nucleosome affect genetic function. The nucleosomes are unevenly spaced, but are well-defined arrangement along the chromatin. The spacing between nucleosomes along the chromosome is critical because DNA in the regions between nucleosome is readily available for interactions with proteins that initiate expression, replication, or further compaction. Even, the way DNA is wounded around nucleosomes seems to play a role in determining whether and how certain proteins interact with specific sequences. This occurs in regular intervals along the DNA molecule that then shortens to fit within the nucleus. Further series of complex packaging, nucleosomes compact into chromatin fiber.
During replication thousands of origins of replication bind to proteins that unwind the two strands of the double-helix. The enzymes DNA polymerase assembles new strings of nucleotides that proceed in a bidirectional matter. As replication continues it is terminated at both ends in protective capped known as telomeres. Composed of DNA associated with proteins, these caps are crucial in preserving the structural integrity on the chromatin. DNA replication also includes the synthesis of histone and nonhistone proteins that are incorporated to regenerate the tissue-specific chromatin structure. Changes in these nuclear proteins produce different folding patterns that promote the expression of different genes. After the chromatin replicate in S phase of the cell cycle, the two sister chromatids are held together at the centromerees, that ensure proper segregation (Figure 3). Through an elaborate structure of kinetochores: specialized structure composed of DNA and proteins that is the site at which chromosomes attach to the spindle fiber during prometaphase. By anaphase the sister chromatids are free to migrate towards opposite pole, with the assistance of the motor proteins shortening in the kinetochore. Ultimately, mitosis and cytokinesis produce two daughter cells having the same genetic information as the mother cell. The development of multicellular organism depends in the consistent repeated process of mitosis and cytokinesis. This sorting process conserves the integrity of the chromatin structure from one cell to the next.
Chromosomal research in the 1930's, stained cells with certain DNA-binding chemicals, and discovered small proportion of chromosome that appeared darker than other when viewed under a light microscope. These darker regions are heterochromatin and the contrasting lighter regions as euchromatin. It revealed that chromatin is present in two distinct phases based on the degree of compaction. Heterochromatin appear to be transcriptionally inactive for the most part of a cell's life because it is so tightly packaged that the enzymes required for transcription of a gene cannot access the DNA sequence. In contrast, euchromatin contain most of the sites of transcription and thus almost all the genes. Heterochromatins are usually found near the centromeres and the edges along the telomeres. These regions play a part in the large integrative system of gene regulation. Not surprisingly chromatin structure plays a key role in gene expression. The structure of chromatin is sufficicent to maintain transcriptional activity at a minimum. The initial component of gene activation is the remodeling of chromatin structure in the promoter region. Specialized proteins modulators that unravel promoter DNA sequences away from the histone core are the agents of this remodeling. These modulators act in concert with other proteins are part of a code-reader complex, so as to allow particular combination of markings on chromatin to attract additional protein complexes that execute an appropriate biological function at the right time (cite cell book pg. 225) Epigenetic modifications such as histone acetlyation occur in the amino terminal tails from the histones that protrude from the nucleosome. They are subject to a wide range of chemical modifications depending on the cell's needs. Acetylation is known to play a key role in the regulation of gene expression. Histone actylation is controlled by the balance and activity of two enzymes: Histone Acetyltransferase (HAT) and Histone Deacetylase (HDAC). The acetylation by HAT uncoils the DNA into an open chromatin structure. This causes genes to become accessible for transcription factors allowing genes expression and protein synthesis to occur. A large variation is found in histone modification. Gene regulatory proteins bind to histone tails that contain specific patterns of chemical modifications. Once a regulatory protein is intact, it governs the fate of the underlying DNA. In addition, histone modification memories can extend into the next set of daughter cells because chromatins have the ability to self-renew the nucleosome modifications inherited from parent cells. These modifications account for changes in a cell's phenotype without altering the nucleotide sequence of DNA, which is one of many examples of epigenetic inheritance.
Figure 2. Nucleosomes are composed of histone core proteins which are tightly wrapped with DNA. Forming a "strings-on-a-beard" that eventually is packaged into chromatin fiber.
As mention before, chromatin is present in two distinct phases: Heterochromatin and Euchromatin. Chromatin alterations facilitate in accessing DNA more readily, thereby allowing transcription factors to assemble at the promoter site. These proteins function as regulatory segments of a larger complex whose function is dependent on all the individual components. The final assembly is primarily composed of control region DNA sequences that interact with particular gene regulatory proteins found in the cell, as shown in Figure 2. Thus, each gene in an organism's genome is regulated by a committee of regulatory proteins, all of which are required to be present for proper levels of expression. The need for a meticulous DNA-protein complex offers another mechanism in controlling levels of gene expression, one that provides enrich opportunities.
Within the nucleus, chromatin is the site of cell memorization, a perquisite for the development of differential tissue. Cell memory arises from molecular mechanisms such as DNA methylation and positive feedback loops. The covalent modification of DNA affords a mechanism to which gene expression patterns are directly passed on to progeny cells. The methylation of cytosine in the CG base pairing has several uses in eukaryotic cells. It's most important function is promoting an efficient gene control mechanism that creates a gene suppression form that is passed to progeny cells. Positive feedback loops are quite simple processes that establish cell memory. Positive feedback loops come about from a transient signal that starts the initial transcription of a protein. All the progeny from the original cell remembers the transient signal and begins to synthesize the protein. This mechanism promotes the continued synthesis of a protein, and at the same time represses gene expression of other proteins. Many regulatory proteins work in this reciprocal manner which creates chemical behaviors that are passed to progeny cells. As cells begin to develop, these mechanisms and many more set forth the tools for cells to differentiate and establish specialized cell types.
The inheritance that a progeny cell receives is chemically embedded in the chromatin. The organism's genome and its epigenetic inheritance are all located within the chromatin fiber. The central processes of the development of multi-cellular organism take place on the chromatin. During the first primordial stages of cellular development, there's a rapid rate of gene regulatory proteins and transmembrane proteins are synthesized. The second class of proteins is used for cell adhesion and cell signaling. As the first cells begin to develop they all share identical genomes and have the same developmental potential. The only relative difference is their locations between one another. These spatial differences seem to be the initial spark in cell differentiation. When cells begin to communicate with one another, they release signaling molecules into the environment. Cells that happen to be close by receive the signal and create an intracellular response. A distance away, other cells are releasing their own signaling molecules as well. Cells that are in close proximity receive the chemical signal. These signaling molecules interact with specific transmembrane proteins that generate secondary signal in the cell that affect gene expression. Secondary signals can activate a wide range of processes. Usually, environmental signals generate secondary messages that alter chromatin structure. For instance, regulatory proteins may be activated and bind to specific histone tails that causes changes in nucleosome configuration that make DNA accessible for transcription. After several cell divisions, cells start to establish a distinct pattern of gene expression and begin to differentiate into cell types. Once a cell becomes a specific cell type it commits to a specific gene pattern that is passed through future cell generations. Progeny cells are able to maintain and memorize chemical behaviors because these characteristics are rooted on the chromatin fiber.