H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri- methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression . The name denotes the addition of three methyl groups ( trimethylation ) to the lysine 4 on the histone H3 protein.
104-539: H3 is used to package DNA in eukaryotic cells (including human cells), and modifications to the histone alter the accessibility of genes for transcription. H3K4me3 is commonly associated with the activation of transcription of nearby genes. H3K4 trimethylation regulates gene expression through chromatin remodeling by the NURF complex. This makes the DNA in the chromatin more accessible for transcription factors , allowing
208-479: A Histone code dictates the expression of genes by a complex interaction between the histones in a particular region. The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap. The purpose of the epigenomic study was to investigate epigenetic changes across the entire genome. This led to chromatin states which define genomic regions by grouping
312-445: A buffer to recruit or titrate ions or antibiotics. Extracellular DNA acts as a functional extracellular matrix component in the biofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm; it may contribute to biofilm formation; and it may contribute to the biofilm's physical strength and resistance to biological stress. Cell-free fetal DNA
416-413: A cell makes up its genome ; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes. The information carried by DNA is held in the sequence of pieces of DNA called genes . Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into
520-450: A chain by covalent bonds (known as the phosphodiester linkage ) between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone . The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules (A with T and C with G), with hydrogen bonds to make double-stranded DNA. The complementary nitrogenous bases are divided into two groups,
624-445: A complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation , which depends on the same interaction between RNA nucleotides. In an alternative fashion, a cell may copy its genetic information in a process called DNA replication . The details of these functions are covered in other articles; here
728-492: A double helix can thus be pulled apart like a zipper, either by a mechanical force or high temperature . As a result of this base pair complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. This reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in organisms. Most DNA molecules are actually two polymer strands, bound together in
832-450: A flexible system of gene expression, in which genes are primarily repressed, but may be expressed quickly due to H3K4me3 as the cell progresses through development. These regions tend to coincide with transcription factor genes expressed at low levels. Some of these factors, such as the Hox genes , are essential for control development and cellular differentiation during embryogenesis . H3K4me3
936-428: A full set of the mitochondrial genes. Each human mitochondrion contains, on average, approximately 5 such mtDNA molecules. Each human cell contains approximately 100 mitochondria, giving a total number of mtDNA molecules per human cell of approximately 500. However, the amount of mitochondria per cell also varies by cell type, and an egg cell can contain 100,000 mitochondria, corresponding to up to 1,500,000 copies of
1040-424: A genome independently of the underlying genome sequence. This independence from the DNA sequence enforces the epigenetic nature of histone modifications. Chromatin states are also useful in identifying regulatory elements that have no defined sequence, such as enhancers . This additional level of annotation allows for a deeper understanding of cell specific gene regulation. The histone mark H3K4me3 can be detected in
1144-489: A genome independently of the underlying genome sequence. This independence from the DNA sequence enforces the epigenetic nature of histone modifications. Chromatin states are also useful in identifying regulatory elements that have no defined sequence, such as enhancers. This additional level of annotation allows for a deeper understanding of cell specific gene regulation. Cause-and-effect relationship between sperm -transmitted histone marks and gene expression and development
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#17327871421451248-439: A helical fashion by noncovalent bonds; this double-stranded (dsDNA) structure is maintained largely by the intrastrand base stacking interactions, which are strongest for G,C stacks. The two strands can come apart—a process known as melting—to form two single-stranded DNA (ssDNA) molecules. Melting occurs at high temperatures, low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH
1352-571: A higher number is also possible but this would be against the natural principle of least effort . The phosphate groups of DNA give it similar acidic properties to phosphoric acid and it can be considered as a strong acid . It will be fully ionized at a normal cellular pH, releasing protons which leave behind negative charges on the phosphate groups. These negative charges protect DNA from breakdown by hydrolysis by repelling nucleophiles which could hydrolyze it. Pure DNA extracted from cells forms white, stringy clumps. The expression of genes
1456-667: A long-standing puzzle known as the " C-value enigma ". However, some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression . Some noncoding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes but are important for the function and stability of chromosomes. An abundant form of noncoding DNA in humans are pseudogenes , which are copies of genes that have been disabled by mutation. These sequences are usually just molecular fossils , although they can occasionally serve as raw genetic material for
1560-409: A narrower, deeper major groove. The A form occurs under non-physiological conditions in partly dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, and in enzyme-DNA complexes. Segments of DNA where the bases have been chemically modified by methylation may undergo a larger change in conformation and adopt the Z form . Here, the strands turn about
1664-511: A protective role by inhibiting non-cell-type specific enhancers. Ultimately, this leads to the inactivation of transcription. Acetylation is usually linked to the upregulation of genes. This is the case in H3K27ac which is an active enhancer mark. It is found in distal and proximal regions of genes. It is enriched in transcriptional start sites (TSS). H3K27ac shares a location with H3K27me3 and they interact in an antagonistic manner. H3K27me3
1768-442: A radius of 10 Å (1.0 nm). According to another study, when measured in a different solution, the DNA chain measured 22–26 Å (2.2–2.6 nm) wide, and one nucleotide unit measured 3.3 Å (0.33 nm) long. The buoyant density of most DNA is 1.7g/cm . DNA does not usually exist as a single strand, but instead as a pair of strands that are held tightly together. These two long strands coil around each other, in
1872-416: A second protein when read in the opposite direction along the other strand. In bacteria , this overlap may be involved in the regulation of gene transcription, while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome. DNA can be twisted like a rope in a process called DNA supercoiling . With DNA in its "relaxed" state, a strand usually circles
1976-445: A simple TTAGGG sequence. These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases, known as a guanine tetrad , form a flat plate. These flat four-base units then stack on top of each other to form a stable G-quadruplex structure. These structures are stabilized by hydrogen bonding between
2080-466: A variety of ways: 1. Chromatin immunoprecipitation sequencing ( ChIP-sequencing ) measures the amount of DNA enrichment once bound to a targeted protein and immunoprecipitated . It results in good optimization and is used in vivo to reveal DNA-protein binding occurring in cells. ChIP-Seq can be used to identify and quantify various DNA fragments for different histone modifications along a genomic region. 2. Micrococcal nuclease sequencing ( MNase-seq )
2184-544: A variety of ways: 1. Chromatin Immunoprecipitation Sequencing ( ChIP sequencing ) measures the amount of DNA enrichment once bound to a targeted protein and immunoprecipitated. It results in good optimization and is used in vivo to reveal DNA-protein binding occurring in cells. ChIP-Seq can be used to identify and quantify various DNA fragments for different histone modifications along a genomic region. 2. Micrococcal Nuclease sequencing (MNase-seq)
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#17327871421452288-413: Is a polymer composed of two polynucleotide chains that coil around each other to form a double helix . The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses . DNA and ribonucleic acid (RNA) are nucleic acids . Alongside proteins , lipids and complex carbohydrates ( polysaccharides ), nucleic acids are one of
2392-447: Is called intercalation . Most intercalators are aromatic and planar molecules; examples include ethidium bromide , acridines , daunomycin , and doxorubicin . For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations. As a result, DNA intercalators may be carcinogens , and in
2496-435: Is called a polynucleotide . The backbone of the DNA strand is made from alternating phosphate and sugar groups. The sugar in DNA is 2-deoxyribose , which is a pentose (five- carbon ) sugar. The sugars are joined by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These are known as the 3′-end (three prime end), and 5′-end (five prime end) carbons,
2600-434: Is dependent on ionic strength and the concentration of DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determines the strength of the association between the two strands of DNA. Long DNA helices with a high GC -content have more strongly interacting strands, while short helices with high AT content have more weakly interacting strands. In biology, parts of
2704-407: Is found in the blood of the mother, and can be sequenced to determine a great deal of information about the developing fetus. H3K27me3 H3K27me3 is an epigenetic modification to the DNA packaging protein histone H3 . It is a mark that indicates the tri- methylation of lysine 27 on histone H3 protein. This tri-methylation is associated with the downregulation of nearby genes via
2808-399: Is however believed to be implicated in all the different methylations associated with H3K27me. H3K27me1 is linked to promotion of transcription and is seen to accumulate in transcribed genes. Histone-histone interactions play a role in this process. Regulation occurs via Setd2-dependent H3K36me3 deposition. H3K27me2 is broadly distributed within the core histone H3 and is believed to play
2912-484: Is in offspring and grandoffspring. H3K27me3 is believed to be implicated in some diseases due to its regulation as a repressive mark. Cohen–Gibson syndrome is a disorder linked to overgrowth and is characterised by dysmorphic facial features and variable intellectual disability. In some cases, a de novo missense mutation in EED was associated with decreased levels of H3K27me3 in comparison to wild type . This decrease
3016-411: Is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin . Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of the histone protein core around which DNA is wrapped in
3120-432: Is introduced by enzymes called topoisomerases . These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication . DNA exists in many possible conformations that include A-DNA , B-DNA , and Z-DNA forms, although only B-DNA and Z-DNA have been directly observed in functional organisms. The conformation that DNA adopts depends on
3224-422: Is nothing special about the four natural nucleobases that evolved on Earth. On the other hand, DNA is tightly related to RNA which does not only act as a transcript of DNA but also performs as molecular machines many tasks in cells. For this purpose it has to fold into a structure. It has been shown that to allow to create all possible structures at least four bases are required for the corresponding RNA , while
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3328-460: Is often seen to interact with H3K4me3 in bivalent domains . These domains are usually found in embryonic stem cells and are pivotal for proper cell differentiation. H3K27me3 and H3K4me3 determine whether a cell will remain unspecified or will eventually differentiate. The Grb10 gene in mice makes use of these bivalent domains. Grb10 displays imprinted gene expression. Genes are expressed from one parental allele while simultaneously being silenced in
3432-432: Is one of four types of nucleobases (or bases ). It is the sequence of these four nucleobases along the backbone that encodes genetic information. RNA strands are created using DNA strands as a template in a process called transcription , where DNA bases are exchanged for their corresponding bases except in the case of thymine (T), for which RNA substitutes uracil (U). Under the genetic code , these RNA strands specify
3536-406: Is present at sites of DNA double-strand breaks where it promotes repair by the non-homologous end joining pathway. It has been implicated that the binding of H3K4me3 is necessary for the function of genes such as inhibitor of growth protein 1 (ING1) , which act as a tumor suppressors and enact DNA repair mechanisms. When DNA damage occurs, DNA damage signalling and repair begins as a result of
3640-517: Is rarely used). The stability of the dsDNA form depends not only on the GC -content (% G,C basepairs) but also on sequence (since stacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured in various ways; a common way is the melting temperature (also called T m value), which is the temperature at which 50% of the double-strand molecules are converted to single-strand molecules; melting temperature
3744-428: Is recreated by an enzyme called DNA polymerase . This enzyme makes the complementary strand by finding the correct base through complementary base pairing and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which base appears on
3848-516: Is the largest human chromosome with approximately 220 million base pairs , and would be 85 mm long if straightened. In eukaryotes , in addition to nuclear DNA , there is also mitochondrial DNA (mtDNA) which encodes certain proteins used by the mitochondria. The mtDNA is usually relatively small in comparison to the nuclear DNA. For example, the human mitochondrial DNA forms closed circular molecules, each of which contains 16,569 DNA base pairs, with each such molecule normally containing
3952-401: Is through comparing the epigenetic pattern to that of embryonic stem cells . In bivalent chromatin , H3K4me3 is co-localized with the repressive modification H3K27me3 to control gene regulation. H3K4me3 in embryonic cells is part of a bivalent chromatin system, in which regions of DNA are simultaneously marked with activating and repressing histone methylations. This is believed to allow for
4056-489: Is to allow the cell to replicate chromosome ends using the enzyme telomerase , as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes. These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected. In human cells , telomeres are usually lengths of single-stranded DNA containing several thousand repeats of
4160-514: Is used as a histone code or histone mark in epigenetic studies (usually identified through chromatin immunoprecipitation ) to identify active gene promoters . H3K4me3 promotes gene activation through the action of the NURF complex, a protein complex that acts through the PHD finger protein motif to remodel chromatin. This makes the DNA in the chromatin accessible for transcription factors , allowing
4264-618: Is used to investigate regions that are bound by well positioned nucleosomes. Use of the micrococcal nuclease enzyme is employed to identify nucleosome positioning. Well positioned nucleosomes are seen to have enrichment of sequences. 3. Assay for transposase accessible chromatin sequencing ( ATAC-seq ) is used to look in to regions that are nucleosome free (open chromatin). It uses hyperactive Tn5 transposon to highlight nucleosome localisation. DNA Deoxyribonucleic acid ( / d iː ˈ ɒ k s ɪ ˌ r aɪ b oʊ nj uː ˌ k l iː ɪ k , - ˌ k l eɪ -/ ; DNA )
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4368-657: The DNA sequence . Mutagens include oxidizing agents , alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays . The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing thymine dimers , which are cross-links between pyrimidine bases. On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks. A typical human cell contains about 150,000 bases that have suffered oxidative damage. Of these oxidative lesions,
4472-589: The EZH inhibiting protein , decreasing PRC2-activity. There is evidence that implicates the downregulation of expression of H3K27me3 in conjunction with differential expression of H3K4me3 AND DNA methylation may play a factor in fetal alcohol spectrum disorder (FASD) in C57BL/6J mice. This histone code is believed to affect the peroxisome associated pathway and induce the loss of the peroxisomes to ameliorate oxidative stress. The histone mark H3K27me3 can be detected in
4576-406: The amino-acid sequences of proteins is determined by the rules of translation , known collectively as the genetic code . The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT). In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase . This RNA copy is then decoded by a ribosome that reads
4680-469: The cell nucleus as nuclear DNA , and some in the mitochondria as mitochondrial DNA or in chloroplasts as chloroplast DNA . In contrast, prokaryotes ( bacteria and archaea ) store their DNA only in the cytoplasm , in circular chromosomes . Within eukaryotic chromosomes, chromatin proteins, such as histones , compact and organize DNA. These compacting structures guide the interactions between DNA and other proteins, helping control which parts of
4784-419: The 3′ and 5′ carbons along the sugar-phosphate backbone confers directionality (sometimes called polarity) to each DNA strand. In a nucleic acid double helix , the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands are antiparallel . The asymmetric ends of DNA strands are said to have a directionality of five prime end (5′ ), and three prime end (3′), with
4888-591: The 5′ end having a terminal phosphate group and the 3′ end a terminal hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by the related pentose sugar ribose in RNA. The DNA double helix is stabilized primarily by two forces: hydrogen bonds between nucleotides and base-stacking interactions among aromatic nucleobases. The four bases found in DNA are adenine ( A ), cytosine ( C ), guanine ( G ) and thymine ( T ). These four bases are attached to
4992-435: The DNA are transcribed. DNA is a long polymer made from repeating units called nucleotides . The structure of DNA is dynamic along its length, being capable of coiling into tight loops and other shapes. In all species it is composed of two helical chains, bound to each other by hydrogen bonds . Both chains are coiled around the same axis, and have the same pitch of 34 ångströms (3.4 nm ). The pair of chains have
5096-460: The DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters , tend to have a high AT content, making the strands easier to pull apart. In the laboratory, the strength of this interaction can be measured by finding the melting temperature T m necessary to break half of the hydrogen bonds. When all the base pairs in a DNA double helix melt,
5200-401: The RNA sequence by base-pairing the messenger RNA to transfer RNA , which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (4 combinations). These encode the twenty standard amino acids , giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are
5304-491: The TAG, TAA, and TGA codons, (UAG, UAA, and UGA on the mRNA). Cell division is essential for an organism to grow, but, when a cell divides, it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication . Here, the two strands are separated and then each strand's complementary DNA sequence
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#17327871421455408-442: The axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound. If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that
5512-407: The canonical bases plus uracil. Twin helical strands form the DNA backbone. Another double helix may be found tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site . As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. The major groove is 22 ångströms (2.2 nm) wide, while
5616-467: The case of thalidomide, a teratogen . Others such as benzo[ a ]pyrene diol epoxide and aflatoxin form DNA adducts that induce errors in replication. Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer cells. DNA usually occurs as linear chromosomes in eukaryotes , and circular chromosomes in prokaryotes . The set of chromosomes in
5720-581: The cell (see below) , but the major and minor grooves are always named to reflect the differences in width that would be seen if the DNA was twisted back into the ordinary B form . In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand. This is called complementary base pairing . Purines form hydrogen bonds to pyrimidines, with adenine bonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds. This arrangement of two nucleotides binding together across
5824-420: The cell and lead to complex, combinatorial transcriptional output. It is thought that a histone code dictates the expression of genes by a complex interaction between the histones in a particular region. The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap. The purpose of the epigenomic study was to investigate epigenetic changes across
5928-619: The chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling ). There is, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression. For one example, cytosine methylation produces 5-methylcytosine , which is important for X-inactivation of chromosomes. The average level of methylation varies between organisms—the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine. Despite
6032-481: The compaction of the chromatin. The inflammatory transcription factor NF-κB can cause demethylation of H3K27me3 via Jmjd3 . H3K27me3 is linked to the repair of DNA damages , particularly repair of double-strand breaks by homologous recombinational repair. H3K27 can undergo a variety of other modifications. It can exist in mono- as well as di-methylated states. The roles of these respective modifications are not as well characterised as tri-methylation. PRC2
6136-480: The conditions found in cells, it is not a well-defined conformation but a family of related DNA conformations that occur at the high hydration levels present in cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a significant degree of disorder. Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and
6240-498: The creation and readout of the H3K4me3 modification. WDR5 activity has been shown to be required for developmental genes, like the Hox genes , that are regulated by histone methylation. H3K4me3 is a commonly used histone modification. H3K4me3 is one of the least abundant histone modifications; however, it is highly enriched at active promoters near transcription start sites (TSS) and positively correlated with transcription. H3K4me3
6344-405: The creation of new genes through the process of gene duplication and divergence . A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and
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#17327871421456448-449: The cytoplasm called the nucleoid . The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype . A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, and regulatory sequences such as promoters and enhancers , which control transcription of
6552-412: The data obtained led to the definition of chromatin states based on histone modifications. Certain modifications were mapped and enrichment was seen to localize in certain genomic regions. Five core histone modifications were found with each respective one being linked to various cell functions. The human genome was annotated with chromatin states. These annotated states can be used as new ways to annotate
6656-405: The double helix (from six-carbon ring to six-carbon ring) is called a Watson-Crick base pair. DNA with high GC-content is more stable than DNA with low GC -content. A Hoogsteen base pair (hydrogen bonding the 6-carbon ring to the 5-carbon ring) is a rare variation of base-pairing. As hydrogen bonds are not covalent , they can be broken and rejoined relatively easily. The two strands of DNA in
6760-442: The edges of the bases and chelation of a metal ion in the centre of each four-base unit. Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure. In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here,
6864-481: The end of an otherwise complementary double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple branches are also possible. Branched DNA can be used in nanotechnology to construct geometric shapes, see
6968-515: The entire genome. This led to chromatin states which define genomic regions by grouping the interactions of different proteins and/or histone modifications together. Chromatin states were investigated in Drosophila cells by looking at the binding location of proteins in the genome. Use of ChIP sequencing revealed regions in the genome characterised by different banding. Different developmental stages were profiled in Drosophila as well, an emphasis
7072-418: The focus is on the interactions between DNA and other molecules that mediate the function of the genome. Genomic DNA is tightly and orderly packed in the process called DNA condensation , to fit the small available volumes of the cell. In eukaryotes, DNA is located in the cell nucleus , with small amounts in mitochondria and chloroplasts . In prokaryotes, the DNA is held within an irregularly shaped body in
7176-485: The formation of heterochromatic regions. H3K27me3 indicates trimethylation of lysine 27 on histone H3 protein subunit: (counting from N-terminus ) This diagram shows the progressive methylation of a lysine residue. The tri-methylation (right) denotes the methylation present in H3K27me3. The genomic DNA of eukaryotic cells is wrapped around special protein molecules known as histones . The complexes formed by
7280-461: The four major types of macromolecules that are essential for all known forms of life . The two DNA strands are known as polynucleotides as they are composed of simpler monomeric units called nucleotides . Each nucleotide is composed of one of four nitrogen-containing nucleobases ( cytosine [C], guanine [G], adenine [A] or thymine [T]), a sugar called deoxyribose , and a phosphate group . The nucleotides are joined to one another in
7384-448: The functions of these RNAs are not entirely clear. One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing. A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses , blur the distinction between sense and antisense strands by having overlapping genes . In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and
7488-653: The genes to be transcribed and expressed in the cell. The genomic DNA of eukaryotic cells is wrapped around special protein molecules known as histones . The complexes formed by the looping of the DNA are known as chromatin . The basic structural unit of chromatin is the nucleosome : this consists of the core octamer of histones (H2A, H2B, H3 and H4) as well as a linker histone and about 180 base pairs of DNA. These core histones are rich in lysine and arginine residues. The carboxyl (C) terminal end of these histones contribute to histone-histone interactions, as well as histone-DNA interactions. The amino (N) terminal charged tails are
7592-587: The genes to be transcribed and expressed in the cell. More specifically, H3K4me3 is found to positively regulate transcription by bringing histone acetylases and nucleosome remodelling enzymes (NURF). H3K4me3 also plays an important role in the genetic regulation of stem cell potency and lineage . This is because this histone modification is found more in areas of the DNA that are associated with development and establishing cell identity. H3K4me3 indicates trimethylation of lysine 4 on histone H3 protein subunit: (counting from N-terminus ) This diagram shows
7696-448: The helical axis in a left-handed spiral, the opposite of the more common B form. These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription. For many years, exobiologists have proposed the existence of a shadow biosphere , a postulated microbial biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One of
7800-448: The hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions , and the presence of polyamines in solution. The first published reports of A-DNA X-ray diffraction patterns —and also B-DNA—used analyses based on Patterson functions that provided only a limited amount of structural information for oriented fibers of DNA. An alternative analysis
7904-427: The hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes. These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging. Many mutagens fit into the space between two adjacent base pairs, this
8008-412: The importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations . Other base modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain , and the glycosylation of uracil to produce the "J-base" in kinetoplastids . DNA can be damaged by many sorts of mutagens , which change
8112-425: The interactions of different proteins and/or histone modifications together. Chromatin states were investigated in Drosophila cells by looking at the binding location of proteins in the genome. Use of ChIP-sequencing revealed regions in the genome characterised by different banding. Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance. A look in to
8216-474: The looping of the DNA are known as chromatin . The basic structural unit of chromatin is the nucleosome : this consists of the core octamer of histones (H2A, H2B, H3 and H4) as well as a linker histone and about 180 base pairs of DNA. These core histones are rich in lysine and arginine residues. The carboxyl (C) terminal end of these histones contribute to histone-histone interactions, as well as histone-DNA interactions. The amino (N) terminal charged tails are
8320-441: The minor groove is 12 Å (1.2 nm) in width. Due to the larger width of the major groove, the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove. This situation varies in unusual conformations of DNA within
8424-516: The mitochondrial genome (constituting up to 90% of the DNA of the cell). A DNA sequence is called a "sense" sequence if it is the same as that of a messenger RNA copy that is translated into protein. The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but
8528-406: The modification of histones within the chromatin. Mechanistically, the demethylation of H3K4me3 is used required for specific protein binding and recruitment to DNA damage The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling complexes are interpreted by the cell and lead to complex, combinatorial transcriptional output. It is thought that
8632-477: The most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations , insertions , deletions from the DNA sequence, and chromosomal translocations . These mutations can cause cancer . Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. DNA damages that are naturally occurring , due to normal cellular processes that produce reactive oxygen species,
8736-464: The new strand, and the cell ends up with a perfect copy of its DNA. Naked extracellular DNA (eDNA), most of it released by cell death, is nearly ubiquitous in the environment. Its concentration in soil may be as high as 2 μg/L, and its concentration in natural aquatic environments may be as high at 88 μg/L. Various possible functions have been proposed for eDNA: it may be involved in horizontal gene transfer ; it may provide nutrients; and it may act as
8840-459: The nucleosomes without directly modifying them. These histone marks can serve as docking sites of other co-activators as seen with H3K27me3. This occurs through polycomb mediated gene silencing via histone methylation and chromodomain interactions. A polycomb repressive complex (PRC); PRC2 , mediates the tri-methylation of histone 3 on lysine 27 through histone methyl transferase activity. This mark can recruit PRC1 which will bind and contribute to
8944-454: The open reading frame. In many species , only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons , with over 50% of human DNA consisting of non-coding repetitive sequences . The reasons for the presence of so much noncoding DNA in eukaryotic genomes and the extraordinary differences in genome size , or C-value , among species, represent
9048-573: The other parental allele. Demethylation of H3K27me3 can lead to up-regulation of genes controlling the senescence-associated secretory phenotype (SASP). Other well characterised modifications are H3K9me3 as well as H4K20me 3 which—just like H3K27me3—are linked to transcriptional repression via formation of heterochromatic regions. Mono-methylations of H3K27, H3K9, and H4K20 are all associated with gene activation. The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling complexes are interpreted by
9152-428: The place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. In addition to RNA and DNA, many artificial nucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology. Modified bases occur in DNA. The first of these recognized was 5-methylcytosine , which was found in the genome of Mycobacterium tuberculosis in 1925. The reason for
9256-530: The presence of these noncanonical bases in bacterial viruses ( bacteriophages ) is to avoid the restriction enzymes present in bacteria. This enzyme system acts at least in part as a molecular immune system protecting bacteria from infection by viruses. Modifications of the bases cytosine and adenine, the more common and modified DNA bases, play vital roles in the epigenetic control of gene expression in plants and animals. A number of noncanonical bases are known to occur in DNA. Most of these are modifications of
9360-412: The prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms a glycosidic bond . Therefore, any DNA strand normally has one end at which there is a phosphate group attached to the 5′ carbon of a ribose (the 5′ phosphoryl) and another end at which there is a free hydroxyl group attached to the 3′ carbon of a ribose (the 3′ hydroxyl). The orientation of
9464-614: The progressive methylation of a lysine residue. The tri-methylation (right) denotes the methylation present in H3K4me3. The H3K4me3 modification is created by a lysine-specific histone methyltransferase (HMT) transferring three methyl groups to histone H3. H3K4me3 is methylated by methyltransferase complexes containing a protein WDR5 , which contains the WD40 repeat protein motif . WDR5 associates specifically with dimethylated H3K4 and allows further methylation by methyltransferases, allowing for
9568-466: The proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA . A report in 2010 of the possibility in the bacterium GFAJ-1 was announced, though the research was disputed, and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules. At the ends of the linear chromosomes are specialized regions of DNA called telomeres . The main function of these regions
9672-432: The section on uses in technology below. Several artificial nucleobases have been synthesized, and successfully incorporated in the eight-base DNA analogue named Hachimoji DNA . Dubbed S, B, P, and Z, these artificial bases are capable of bonding with each other in a predictable way (S–B and P–Z), maintain the double helix structure of DNA, and be transcribed to RNA. Their existence could be seen as an indication that there
9776-431: The sequence of amino acids within proteins in a process called translation . Within eukaryotic cells, DNA is organized into long structures called chromosomes . Before typical cell division , these chromosomes are duplicated in the process of DNA replication, providing a complete set of chromosomes for each daughter cell. Eukaryotic organisms ( animals , plants , fungi and protists ) store most of their DNA inside
9880-476: The shape of a double helix . The nucleotide contains both a segment of the backbone of the molecule (which holds the chain together) and a nucleobase (which interacts with the other DNA strand in the helix). A nucleobase linked to a sugar is called a nucleoside , and a base linked to a sugar and to one or more phosphate groups is called a nucleotide . A biopolymer comprising multiple linked nucleotides (as in DNA)
9984-552: The single-ringed pyrimidines and the double-ringed purines . In DNA, the pyrimidines are thymine and cytosine; the purines are adenine and guanine. Both strands of double-stranded DNA store the same biological information . This information is replicated when the two strands separate. A large part of DNA (more than 98% for humans) is non-coding , meaning that these sections do not serve as patterns for protein sequences . The two strands of DNA run in opposite directions to each other and are thus antiparallel . Attached to each sugar
10088-502: The single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins. At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop . In DNA, fraying occurs when non-complementary regions exist at
10192-425: The site of the post-translational modifications , such as the one seen in H3K27me3. The placement of a repressive mark on lysine 27 requires the recruitment of chromatin regulators by transcription factors . These modifiers are either histone modification complexes which covalently modify the histones to move around the nucleosomes and open the chromatin, or chromatin remodelling complexes which involve movement of
10296-514: The site of the post-translational modifications, such as the one seen in H3K4me1. Regulation of gene expression through H3K4me3 plays a significant role in stem cell fate determination and early embryo development. Pluripotent cells have distinctive patterns of methylation that can be identified through ChIP-seq . This is important in the development of induced pluripotent stem cells . A way of finding indicators of successful pluripotent induction
10400-518: The strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others. In humans, the total female diploid nuclear genome per cell extends for 6.37 Gigabase pairs (Gbp), is 208.23 cm long and weighs 6.51 picograms (pg). Male values are 6.27 Gbp, 205.00 cm, 6.41 pg. Each DNA polymer can contain hundreds of millions of nucleotides, such as in chromosome 1 . Chromosome 1
10504-469: The sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate . Adenine pairs with thymine and guanine pairs with cytosine, forming A-T and G-C base pairs . The nucleobases are classified into two types: the purines , A and G , which are fused five- and six-membered heterocyclic compounds , and the pyrimidines , the six-membered rings C and T . A fifth pyrimidine nucleobase, uracil ( U ), usually takes
10608-418: Was linked to loss of PRC2 activity. Diffuse midline glioma, H3K27me3-altered (DMG), also known as diffuse intrinsic pontine glioma (DIPG) is a type of highly aggressive brain tumor mostly found in children. All DMGs exhibit loss of H3K27me3, in about 80% of cases due to a genetic mutation receplacing lysine with methionine (M), known as H3K27M. In rare forms, H3Kme3-loss is mediated by overexpression of
10712-473: Was placed on histone modification relevance. A look in to the data obtained led to the definition of chromatin states based on histone modifications. Certain modifications were mapped and enrichment was seen to localize in certain genomic regions. Five core histone modifications were found with each respective one being linked to various cell functions. The human genome was annotated with chromatin states. These annotated states can be used as new ways to annotate
10816-526: Was proposed by Wilkins et al. in 1953 for the in vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions . In the same journal, James Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double helix. Although the B-DNA form is most common under
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