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120-412: Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail , H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of

240-428: A bromodomain , a 110-amino acid module that recognizes acetylated lysine residues and is functionally linked to the co-activators in the regulation of transcription. The ability of histone acetyltransferases to manipulate chromatin structure and lay an epigenetic framework makes them essential in cell maintenance and survival. The process of chromatin remodeling involves several enzymes, including HATs, that assist in

360-402: A ping-pong mechanism involving conserved glutamate and cysteine residues. The first part of the reaction involves the formation of a covalent intermediate in which a cysteine residue becomes acetylated following nucleophilic attack of this residue on the carbonyl carbon of acetyl-CoA. Then, a glutamate residue acts as a general base to facilitate transfer of the acetyl group from the cysteine to

480-549: A vise , with the central core of the protein at the base and the N- and C-terminal segments on the sides. The p300/CBP HATs have larger HAT domains (about 500 residues) than those present in the GNAT and MYST families. They also contain a bromodomain as well as three cysteine/histidine-rich domains that are thought to mediate interactions with other proteins. The structure of p300/CBP is characterized by an elongated globular domain, which contains

600-404: A ' helix turn helix turn helix' motif (DNA-binding protein motif that recognize specific DNA sequence). They also share the feature of long 'tails' on one end of the amino acid structure - this being the location of post-translational modification (see below). Archaeal histone only contains a H3-H4 like dimeric structure made out of a single type of unit. Such dimeric structures can stack into

720-551: A 19-aa peptide (preOGP). This is converted into OGP through the cleavage of 5 amino-terminal residues. It is found in human and rat circulation as well as regenerating bone marrow. In blood serum it is bound to α2M along with two other binding proteins that are not clearly identified. A specific receptor has not been identified, but some signaling pathways involved in its bone-regenaration function has been elucidated. Eukaryotic organisms can produce small amounts of specialized variant core histones that differ in amino acid sequence from

840-489: A C-terminal activation domain that is functional in the absence of the HAT domain. In addition to those that are members of the GNAT and MYST families, there are several other proteins found typically in higher eukaryotes that exhibit HAT activity. These include p300/CBP, nuclear receptor coactivators (e.g., ACTR/SRC-1), TAF II 250, TFIIIC, Rtt109, and CLOCK . p300/CBP are metazoan -specific and contain several zinc finger regions,

960-460: A bromodomain, a catalytic (HAT) domain, and regions that interact with other transcription factors. Importantly, the HAT domain shows no sequence homology to other known HATs, and it is required for p300/CBP to function in transcriptional activation. In addition, these proteins contain several HAT domain motifs (A, B, and D) that are similar to those of the GNATs. They also possess a novel motif E that

1080-723: A bromodomain, as their targets are unacetylated. The acetyl groups added by type B HATs to the histones are removed by HDACs once they enter the nucleus and are incorporated into chromatin . Hat1 is one of the few known examples of a type B HAT. Despite this historical classification of HATs, some HAT proteins function in multiple complexes or locations and would thus not easily fit into a particular class. HATs can be grouped into several different families based on sequence homology as well as shared structural features and functional roles. The Gcn5-related N -acetyltransferase (GNAT) family includes Gcn5, PCAF , Hat1, Elp3 , Hpa2, Hpa3, ATF-2 , and Nut1. These HATs are generally characterized by

1200-439: A conserved active site lysine residue, and this modification is required for their function in vivo . Human p300 contains a highly basic loop embedded in the middle of its HAT domain that is hyperacetylated in the active form of the enzyme. It has been proposed that, upon autoacetylation, this loop is released from the electronegative substrate binding site where it sits in the inactive HAT. Acetylation of yeast Rtt109 at Lys290

1320-639: A context-dependent manner. HATs act as transcriptional co-activators or gene silencers and are most often found in large complexes made up of 10 to 20 subunits, some of which shared among different HAT complexes. These complexes include SAGA (Spt/Ada/Gcn5L acetyltransferase), PCAF, ADA (transcriptional adaptor), TFIID (transcription factor II D), TFTC (TBP-free TAF-containing complex), and NuA3/NuA4 (nucleosomal acetyltransferases of H3 and H4). These complexes modulate HAT specificity by bringing HATs to their target genes where they can then acetylate nucleosomal histones. Some HAT transcriptional co-activators contain

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1440-470: A core promoter prevents the initiation of transcription in vitro, and Michael Grunstein demonstrated that histones repress transcription in vivo, leading to the idea of the nucleosome as a general gene repressor. Relief from repression is believed to involve both histone modification and the action of chromatin-remodeling complexes. Vincent Allfrey and Alfred Mirsky had earlier proposed a role of histone modification in transcriptional activation, regarded as

1560-522: A free enzyme. This happens to be the case as well for Sas3, which is observed to acetylate H3K9 and H3K14 in vivo as well as lysine residues on H2A and H4. MOZ can also acetylate H3K14. p300/CBP acetylate all four nucleosomal core histones equally well. In vitro , they have been observed to acetylate H2AK5, H2BK12, H2BK15, H3K14, H3K18, H4K5, and H4K8. SRC-1 acetylates H3K9 and H3K14, TAF II 230 (Drosophila homolog of human TAF II 250) acetylates H3K14, and Rtt109 acetylates H3K9, H3K23, and H3K56 in

1680-456: A free histone or within a nucleosome. Hat1 acetylates H4K5 and H4K12, and Hpa2 acetylates H3K14 in vitro . In flies, acetylation of H4K16 on the male X chromosome by MOF in the context of the MSL complex is correlated with transcriptional upregulation as a mechanism for dosage compensation in these organisms. In humans, the MSL complex carries out the majority of genome-wide H4K16 acetylation. In

1800-438: A high degree of homology throughout their sequences. These proteins have a 400-residue N-terminal region that is absent in yeast Gcn5, but their HAT functions are evolutionarily conserved with respect to the latter. Hat1 was the first HAT protein to be identified. It is responsible for most of the cytoplasmic HAT activity in yeast, and it binds strongly to histone H4 by virtue of its association with an additional subunit, Hat2. Elp3

1920-461: A high level of specificity can be achieved in triggering specific responses. An example of this specificity is when histone H4 is acetylated at lysines 5 and 12. This acetylation pattern has been seen during histone synthesis. Another example is acetylation of H4K16, which has been associated with dosage compensation of the male X chromosome in Drosophila melanogaster . Histone modifications modulate

2040-569: A higher number of histone variants providing a variety of different functions. Recent data are accumulating about the roles of diverse histone variants highlighting the functional links between variants and the delicate regulation of organism development. Histone variants proteins from different organisms, their classification and variant specific features can be found in "HistoneDB 2.0 - Variants" database. Several pseudogenes have also been discovered and identified in very close sequences of their respective functional ortholog genes. The following

2160-593: A left-handed super-helical turn to give a particle of around 100 Angstroms across. The linker histone H1 binds the nucleosome at the entry and exit sites of the DNA, thus locking the DNA into place and allowing the formation of higher order structure. The most basic such formation is the 10 nm fiber or beads on a string conformation. This involves the wrapping of DNA around nucleosomes with approximately 50 base pairs of DNA separating each pair of nucleosomes (also referred to as linker DNA ). Higher-order structures include

2280-443: A mechanism that is different from that of the other HATs. The yeast enzyme has very low catalytic activity in the absence of the histone chaperone proteins Asf1 and Vps75, which may be involved in delivering histone substrates to the enzyme for acetylation. Moreover, a general acid or base have not yet been identified for this HAT. The structures of several HAT domains bound to acetyl-CoA and histone substrate peptides reveal that

2400-508: A molecular manifestation of epigenetics. Michael Grunstein and David Allis found support for this proposal, in the importance of histone acetylation for transcription in yeast and the activity of the transcriptional activator Gcn5 as a histone acetyltransferase. The discovery of the H5 histone appears to date back to the 1970s, and it is now considered an isoform of Histone H1 . Histone acetyltransferase In general, histone acetylation

2520-479: A multisubunit complex in which the other subunits are necessary for them to modify histone residues around the binding site. These enzymes can also modify non-histone proteins. Histone acetyltransferases serve many biological roles inside the cell. Chromatin is a combination of proteins and DNA found in the nucleus , and it undergoes many structural changes as different cellular events such as DNA replication , DNA repair , and transcription occur. Chromatin in

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2640-782: A post-translational modification, and binding domains such as BRCT have been characterised. Most well-studied histone modifications are involved in control of transcription. Two histone modifications are particularly associated with active transcription: Three histone modifications are particularly associated with repressed genes: Analysis of histone modifications in embryonic stem cells (and other stem cells) revealed many gene promoters carrying both H3K4Me3 and H3K27Me3 , in other words these promoters display both activating and repressing marks simultaneously. This peculiar combination of modifications marks genes that are poised for transcription; they are not required in stem cells, but are rapidly required after differentiation into some lineages. Once

2760-612: A quaternary complex. This octameric complex, in association with the 147 base pairs of DNA coiled around it, forms the nucleosome . Histone H1 locks the nucleosome complex together, and it is the last protein to bind in the complex. Histones tend to be positively charged proteins with N-terminal tails that stem from the core. The phosphodiester backbone of DNA is negative, which allows for strong ionic interactions between histone proteins and DNA. Histone acetyltransferases transfer an acetyl group to specific lysine residues on histones, which neutralizes their positive charge and thus reduces

2880-488: A seven-stranded β-sheet in the center that is surrounded by nine α-helices and several loops. The structure of the central core region associated with acetyl-CoA binding is conserved with respect to GNAT and MYST HATs, but there are many structural differences in the regions flanking this central core. Overall, the structural data is consistent with the fact that p300/CBP HATs are more promiscuous than GNAT and MYST HATs with respect to substrate binding. The structure of Rtt109

3000-411: A specific class of major histones but also have their own feature that is distinct from the major histones. These minor histones usually carry out specific functions of the chromatin metabolism. For example, histone H3-like CENPA is associated with only the centromere region of the chromosome. Histone H2A variant H2A.Z is associated with the promoters of actively transcribed genes and also involved in

3120-423: A tag for the binding of proteins that contain areas which recognize the acetylated tails. Secondly, it can block the function of chromatin remodelers. Thirdly, it neutralizes the positive charge on lysines. Acetylation of histone H4 on lysine 16 ( H4K16ac ) is especially important for chromatin structure and function in a variety of eukaryotes and is catalyzed by specific histone lysine acetyltransferases (HATs). H4K16

3240-964: A tall superhelix ("hypernucleosome") onto which DNA coils in a manner similar to nucleosome spools. Only some archaeal histones have tails. The distance between the spools around which eukaryotic cells wind their DNA has been determined to range from 59 to 70 Å. In all, histones make five types of interactions with DNA: The highly basic nature of histones, aside from facilitating DNA-histone interactions, contributes to their water solubility. Histones are subject to post translational modification by enzymes primarily on their N-terminal tails, but also in their globular domains. Such modifications include methylation , citrullination , acetylation , phosphorylation , SUMOylation , ubiquitination , and ADP-ribosylation . This affects their function of gene regulation. In general, genes that are active have less bound histone, while inactive genes are highly associated with histones during interphase . It also appears that

3360-452: A three-stranded β-sheet followed by a long α-helix parallel to and spanning one side of it. The core region, which corresponds to motifs A, B, and D of the GNAT proteins, is flanked on opposite sides by N- and C-terminal α/β segments that are structurally unique for a given HAT family. The central core and the flanking segments together form a cleft over the former, which is where histone substrates can bind prior to catalysis. While

3480-424: A transformation. Members of the GNAT family have a conserved glutamate residue that acts as a general base for catalyzing the nucleophilic attack of the lysine amine on the acetyl-CoA thioester bond. These HATs use an ordered sequential bi-bi mechanism wherein both substrates (acetyl-CoA and histone) must bind to form a ternary complex with the enzyme before catalysis can occur. Acetyl-CoA binds first, followed by

3600-467: A very informative mark and dominates the known histone modification functions. Recently it has been shown, that the addition of a serotonin group to the position 5 glutamine of H3, happens in serotonergic cells such as neurons. This is part of the differentiation of the serotonergic cells. This post-translational modification happens in conjunction with the H3K4me3 modification. The serotonylation potentiates

3720-485: Is a list of human histone proteins, genes and pseudogenes: The nucleosome core is formed of two H2A-H2B dimers and a H3-H4 tetramer, forming two nearly symmetrical halves by tertiary structure ( C2 symmetry; one macromolecule is the mirror image of the other). The H2A-H2B dimers and H3-H4 tetramer also show pseudodyad symmetry. The 4 'core' histones (H2A, H2B, H3 and H4) are relatively similar in structure and are highly conserved through evolution , all featuring

Histone H4 - Misplaced Pages Continue

3840-621: Is a transcription factor which activates histone gene transcription on chromosomes 1 and 6 of human cells. NPAT is also a substrate of cyclin E-Cdk2, which is required for the transition between G1 phase and S phase. NPAT activates histone gene expression only after it has been phosphorylated by the G1/S-Cdk cyclin E-Cdk2 in early S phase. This shows an important regulatory link between cell-cycle control and histone synthesis. Histones were discovered in 1884 by Albrecht Kossel . The word "histone" dates from

3960-435: Is also required for it to exhibit full catalytic activity. Some HATs are also inhibited by acetylation. For example, the HAT activity of the nuclear receptor coactivator ACTR is inhibited upon acetylation by p300/CBP. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are recruited to their target promoters through physical interactions with sequence-specific transcription factors. They usually function within

4080-585: Is an oncogene found in humans. Esa1 was the first essential HAT to be found in yeast, and MOF is its homolog in fruit flies. The HAT activity of the latter is required for the twofold increased transcription of the male X chromosome ( dosage compensation ) in flies. Human HBO1 (HAT bound to ORC1) was the first HAT shown to associate with components of the origin of replication complex . MORF (MOZ-related factor) exhibits very close homology to MOZ throughout its entire length. It contains an N-terminal repression region that decreases its HAT activity in vitro as well as

4200-598: Is an example of a type A HAT found in yeast. It is part of the RNA polymerase II holoenzyme and plays a role in transcriptional elongation . The MYST family of HATs is named after its four founding members MOZ , Ybf2 (Sas3), Sas2, and Tip60 . Other important members include Esa1 , MOF , MORF , and HBO1 . These HATs are typically characterized by the presence of zinc fingers and chromodomains , and they are found to acetylate lysine residues on histones H2A , H3, and H4. Several MYST family proteins contain zinc fingers as well as

4320-435: Is another nuclear receptor coactivator with HAT activity, and it also interacts with p300/CBP. A table summarizing the different families of HATs along with their associated members, parent organisms, multisubunit complexes, histone substrates, and structural features is presented below. HAT-A2 (nuclear receptor coactivators) In general, HATs are characterized by a structurally conserved core region made up of

4440-404: Is called garcinol. This compound is found within the rinds of the garcinia indica fruit, otherwise known as mangosteen . To explore the effects of garcinol on histone acetyltransferases, researchers used HeLa cells. The cells underwent irradiation, creating double-strand breaks within the DNA, and garcinol was introduced into the cells to see if it influenced the DNA damage response. If garcinol

4560-436: Is found in most GNATs, but it is not present in the majority of other known HATs. The yeast Gcn5 (general control nonderepressible-5) HAT is one of the best-characterized members of this family. It has four functional domains, including an N-terminal domain, a highly conserved catalytic (HAT) domain, an Ada2 interaction domain, and a C-terminal bromodomain. PCAF (p300/CBP-associated factor) and GCN5 are mammalian GNATs that share

4680-432: Is homologous to sequences in the HAT domains of GNATs. TFIIIC is one of the general transcription factors involved in RNA polymerase III -mediated transcription. Three components in the human protein have been shown to possess independent HAT activity ( hTFIIIC220 , hTFIIIC110 , and hTFIIIC90 ). Rtt109 is a fungal -specific HAT that requires association with histone chaperone proteins for activity. The HAT activities of

4800-739: Is hypoacetylated at a lysine 16 residue (H4K16) and this defect is due to reduced association of histone acetyltransferase, Mof, to the nuclear matrix Spinocerebellar ataxia type 1 is a neurodegenerative disease that arises as a result of a defective mutant Ataxin-1 protein. Mutant Ataxin-1 reduces histone acetylation resulting in repressed histone acetyltransferase-mediated transcription . HATs have also been associated with control of learning and memory functions. Studies have shown that mice without PCAF or CBP display evidence of neurodegeneration . Mice with PCAF deletion are incompetent with respect to learning, and those with CBP deletion seem to suffer from long-term memory loss. The misregulation of

4920-620: Is known to interact with p300/CBP and PCAF, and its HAT domain is located in its C-terminal region. ACTR (also known as RAC3, AIB1, and TRAM-1 in humans) shares significant sequence homology with SRC-1, in particular in the N-terminal and C-terminal (HAT) regions as well as in the receptor and coactivator interaction domains. ACTR also interacts with p300/CBP and PCAF. The former can prevent ACTR from binding to and activating its receptor by acetylating it in its receptor interaction domain. TIF-2 (transcriptional intermediary factor 2; also known as GRIP1)

Histone H4 - Misplaced Pages Continue

5040-691: Is linked to transcriptional activation and associated with euchromatin . Euchromatin, which is less densely compact, allows transcription factors to bind more easily to regulatory sites on DNA, causing transcriptional activation. When it was first discovered, it was thought that acetylation of lysine neutralizes the positive charge normally present, thus reducing affinity between histone and (negatively charged) DNA, which renders DNA more accessible to transcription factors . Research has emerged, since, to show that lysine acetylation and other posttranslational modifications of histones generate binding sites for specific protein–protein interaction domains, such as

5160-405: Is not the only regulatory post-translational modification to histones that dictates chromatin structure; methylation, phosphorylation, ADP-ribosylation, and ubiquitination have also been reported. These combinations of different covalent modifications on the N-terminal tails of histones have been referred to as the histone code , and it is thought that this code may be heritable and preserved in

5280-483: Is particularly interesting because this is the only acetylatable site of the H4 N-terminal tail, and can influence the formation of a compact higher-order chromatin structure. Hypoacetylation of H4K16 appears to cause delayed recruitment of DNA repair proteins to sites of DNA damage in a mouse model of the premature aging syndrome Hutchinson Gilford progeria . H4K16Ac also has roles in transcriptional activation and

5400-525: Is reduced to about 9 micrometers (0.09 mm) of 30 nm diameter chromatin fibers. There are five families of histones, which are designated H1/H5 (linker histones), H2, H3, and H4 (core histones). The nucleosome core is formed of two H2A-H2B dimers and a H3-H4 tetramer . The tight wrapping of DNA around histones, is to a large degree, a result of electrostatic attraction between the positively charged histones and negatively charged phosphate backbone of DNA. Histones may be chemically modified through

5520-431: Is regulated by two types of mechanisms: (1) interaction with regulatory protein subunits and (2) autoacetylation. A given HAT may be regulated in multiple ways, and the same effector may actually lead to different outcomes under different conditions. Although it is clear that the association of HATs with multiprotein complexes provides a mechanism for the regulation of both HAT activity and substrate specificity in vivo ,

5640-499: Is the synthesis of histone proteins: H1, H2A, H2B, H3, H4. These proteins are synthesized during S phase of the cell cycle. There are different mechanisms which contribute to the increase of histone synthesis. Yeast carry one or two copies of each histone gene, which are not clustered but rather scattered throughout chromosomes. Histone gene transcription is controlled by multiple gene regulatory proteins such as transcription factors which bind to histone promoter regions. In budding yeast,

5760-401: Is this helical structure that allows for interaction between distinct dimers, particularly in a head-tail fashion (also called the handshake motif). The resulting four distinct dimers then come together to form one octameric nucleosome core, approximately 63 Angstroms in diameter (a solenoid (DNA) -like particle). Around 146 base pairs (bp) of DNA wrap around this core particle 1.65 times in

5880-418: Is thought to relax condensed heterochromatin as the negative charge of acetyl groups can repel the DNA phosphate backbone charges, thus reducing the histone binding affinity for DNA. This hypothesis was validated by the discovery of the histone acetyltransferase (HAT) activity of several transcriptional activator complexes. Histone acetylation influences chromatin structure in several ways. First, it can provide

6000-399: Is very similar to that of p300, despite there only being 7% sequence identity between the two proteins. There is a seven-stranded β-sheet that is surrounded by α-helices as well as a loop that is involved in acetyl-CoA substrate binding. Despite the conserved structure, Rtt109 and p300/CBP are functionally unique. For instance, the substrate binding site of the former is more similar to that of

6120-751: The 3'hExo nuclease. SLBP levels are controlled by cell-cycle proteins, causing SLBP to accumulate as cells enter S phase and degrade as cells leave S phase. SLBP are marked for degradation by phosphorylation at two threonine residues by cyclin dependent kinases, possibly cyclin A/ cdk2, at the end of S phase. Metazoans also have multiple copies of histone genes clustered on chromosomes which are localized in structures called Cajal bodies as determined by genome-wide chromosome conformation capture analysis (4C-Seq). Nuclear protein Ataxia-Telangiectasia (NPAT), also known as nuclear protein coactivator of histone transcription,

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6240-519: The 30 nm fiber (forming an irregular zigzag) and 100 nm fiber, these being the structures found in normal cells. During mitosis and meiosis, the condensed chromosomes are assembled through interactions between nucleosomes and other regulatory proteins. Histones are subdivided into canonical replication-dependent histones, whose genes are expressed during the S-phase of the cell cycle and replication-independent histone variants , expressed during

6360-496: The C-domain, and to the N-terminal substrate recognition domain of Clp/Hsp100 proteins. Despite the differences in their topology, these three folds share a homologous helix-strand-helix (HSH) motif. It's also proposed that they may have evolved from ribosomal proteins ( RPS6 / RPS15 ), both being short and basic proteins. Archaeal histones may well resemble the evolutionary precursors to eukaryotic histones. Histone proteins are among

6480-471: The DNA in the nucleus of higher organisms. Bonner and his postdoctoral fellow Ru Chih C. Huang showed that isolated chromatin would not support RNA transcription in the test tube, but if the histones were extracted from the chromatin, RNA could be transcribed from the remaining DNA. Their paper became a citation classic. Paul T'so and James Bonner had called together a World Congress on Histone Chemistry and Biology in 1964, in which it became clear that there

6600-433: The DNA, making it more accessible for gene expression. Five major families of histone proteins exist: H1/H5 , H2A , H2B , H3 , and H4 . Histones H2A, H2B, H3 and H4 are known as the core or nucleosomal histones, while histones H1/H5 are known as the linker histones. The core histones all exist as dimers , which are similar in that they all possess the histone fold domain: three alpha helices linked by two loops. It

6720-545: The FosB promoter in the nucleus accumbens of the brain, causing 61% increase in FosB expression. This would also increase expression of the splice variant Delta FosB . In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction . About 7% of the US population is addicted to alcohol . In rats exposed to alcohol for up to 5 days, there

6840-431: The GNAT and MYST HATs. In addition, the residues in the active site of each enzyme are distinct, which suggests that they employ different catalytic mechanisms for acetyl group transfer. The basic mechanism catalyzed by HATs involves the transfer of an acetyl group from acetyl-CoA to the ε-amino group of a target lysine side-chain within a histone. Different families of HATs employ unique strategies in order to effect such

6960-496: The GNAT and MYST families as well as Rtt109 exhibit greater substrate selectivity than p300/CBP, which is rather promiscuous with regard to substrate binding. Whereas it appears that only three to five residues on either side of the lysine to be acetylated are necessary for effective substrate binding and catalysis by members of the GNAT and p300/CBP families, more distal regions of the substrate may be important for efficient acetylation by MYST family HATs. Different HATs, usually in

7080-500: The H4 core globular domain (involved in protein-protein interaction) or C-terminal tail (involved in post-translational modification). The Osteogenic Growth Peptide (OGP) is a 14-aa peptide produced from alternative translation of histone H4 mRNA, sharing the C-terminal sequence ALKRQGRTLYGFGG of histone H4. Translation is initiated at the 85th amino acid of the histone H4 mRNA, resulting in

7200-506: The MYST family have HAT domains that are about 250 residues in length. Many MYST proteins also contain a cysteine-rich, zinc-binding domain within the HAT region in addition to an N-terminal chromodomain, which binds to methylated lysine residues . On a broader scale, the structures of the catalytic domains of GNAT proteins (Gcn5, PCAF) exhibit a mixed α/β globular fold with a total of five α-helices and six β-strands. The overall topology resembles

7320-628: The N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes. Histone H4 is encoded in multiple genes at different loci including: HIST1H4A , HIST1H4B , HIST1H4C , HIST1H4D , HIST1H4E , HIST1H4F , HIST1H4G , HIST1H4H , HIST1H4I , HIST1H4J , HIST1H4K , HIST1H4L , HIST2H4A , HIST2H4B , HIST4H4 . Histone proteins are among

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7440-469: The ability to acetylate multiple sites in both histones H2B and H3 when it joins other subunits to form the SAGA and ADA complexes. Moreover, the acetylation site specificity of Rtt109 is dictated by its association with either Vps75 or Asf1. When in complex with the former, Rtt109 acetylates H3K9 and H3K27, but, when in complex with the latter, it preferentially acetylates H3K56. The catalytic activity of HATs

7560-443: The acetyllysine-binding bromodomain . Histone acetyltransferases can also acetylate non-histone proteins, such as nuclear receptors and other transcription factors to facilitate gene expression. HATs are traditionally divided into two different classes based on their subcellular localization. Type A HATs are located in the nucleus and are involved in the regulation of gene expression through acetylation of nucleosomal histones in

7680-437: The action of enzymes to regulate gene transcription. The most common modifications are the methylation of arginine or lysine residues or the acetylation of lysine. Methylation can affect how other proteins such as transcription factors interact with the nucleosomes. Lysine acetylation eliminates a positive charge on lysine thereby weakening the electrostatic attraction between histone and DNA, resulting in partial unwinding of

7800-666: The androgen and estrogen (α) receptors, GATA-2, GATA-3 , MyoD, E2F(1-3), p73 α, retinoblastoma (Rb), NF-κB (p50, p65), Smad7 , importin-α , Ku70, YAP1 , E1A adenovirus protein, and S-HDAg ( hepatitis delta virus small delta antigen). p300/CBP have also been observed to acetylate β-catenin , RIP140 , PCNA , the DNA metabolic enzymes flap endonuclease-1 , thymine DNA glycosylase , and Werner syndrome DNA helicase , STAT6 , Runx1 (AML1) , UBF, Beta2/NeuroD, CREB , c-Jun , C/EBPβ, NF-E2 , SREBP , IRF2, Sp3 , YY1, KLF13, EVI1, BCL6 , HNF-4 , ER81 and FOXO4 (AFX) . The formation of multisubunit complexes has been observed to modulate

7920-524: The binding of the general transcription factor TFIID to the TATA box . What was said above of the chemistry of lysine methylation also applies to arginine methylation, and some protein domains—e.g., Tudor domains—can be specific for methyl arginine instead of methyl lysine. Arginine is known to be mono- or di-methylated, and methylation can be symmetric or asymmetric, potentially with different meanings. Enzymes called peptidylarginine deiminases (PADs) hydrolyze

8040-528: The biochemical characteristics of individual histones did not reveal how the histones interacted with each other or with DNA to which they were tightly bound. Also in the 1960s, Vincent Allfrey and Alfred Mirsky had suggested, based on their analyses of histones, that acetylation and methylation of histones could provide a transcriptional control mechanism, but did not have available the kind of detailed analysis that later investigators were able to conduct to show how such regulation could be gene-specific. Until

8160-402: The brain are of central importance in addictions. Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions. Cigarette smokers (about 15% of the US population) are usually addicted to nicotine . After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at

8280-482: The candidate gene for activation of histone gene expression is SBF. SBF is a transcription factor that is activated in late G1 phase, when it dissociates from its repressor Whi5 . This occurs when Whi5 is phosphorylated by Cdc8 which is a G1/S Cdk. Suppression of histone gene expression outside of S phases is dependent on Hir proteins which form inactive chromatin structure at the locus of histone genes, causing transcriptional activators to be blocked. In metazoans

8400-520: The catalytic HAT subunit can carry out histone acetylation more effectively. In addition, the formation of multisubunit HAT complexes influences the lysine specificity of HATs. The specific lysine residues that a given HAT acetylates may become either broader or more restricted in scope upon association with its respective complex. For example, the lysine specificity of MYST family HATs toward their histone substrates becomes more restricted when they associate with their complexes. In contrast, Gcn5 acquires

8520-455: The catalytic activity of p300/CBP and PCAF in vitro . The human premature aging syndrome Hutchinson Gilford progeria is caused by a mutational defect in the processing of lamin A , a nuclear matrix protein. In a mouse model of this condition, recruitment of repair proteins to sites of DNA damage is delayed. The molecular mechanism underlying this delayed repair response involves a histone acetylation defect. Specifically, histone H4

8640-411: The cell can be found in two states: condensed and uncondensed. The latter, known as euchromatin , is transcriptionally active, whereas the former, known as heterochromatin , is transcriptionally inactive. Histones comprise the protein portion of chromatin. There are five different histone proteins: H1, H2A, H2B, H3, and H4. A core histone is formed when two of each histone subtype, excluding H1, form

8760-424: The cell starts to differentiate, these bivalent promoters are resolved to either active or repressive states depending on the chosen lineage. Marking sites of DNA damage is an important function for histone modifications. Without a repair marker, DNA would get destroyed by damage accumulated from sources such as the ultraviolet radiation of the sun. Epigenetic modifications of histone tails in specific regions of

8880-457: The central core domain (motif A in GNATs) is involved in acetyl-CoA binding and catalysis, the N- and C-terminal segments assist in binding histone substrates. Unique features related to the sequence and/or structure of the N- and C-terminal regions for different HAT families may help to explain some observed differences among HATs in histone substrate specificity. CoA binding has been observed to widen

9000-509: The chemistry of the histone; methylation leaves the charge of the lysine intact and adds a minimal number of atoms so steric interactions are mostly unaffected. However, proteins containing Tudor, chromo or PHD domains, amongst others, can recognise lysine methylation with exquisite sensitivity and differentiate mono, di and tri-methyl lysine, to the extent that, for some lysines (e.g.: H4K20) mono, di and tri-methylation appear to have different meanings. Because of this, lysine methylation tends to be

9120-779: The compact Histone octamer core. Histone H4 is one of the slowest evolving proteins. There are H4 genes that are constitutively expressed throughout the cell cycle that encode for proteins that are identical in sequence to the major H4. Variants in human histone H4 were only recently discovered and are very rare. Pathogenic de novo missense variants have been identified in six H4 genes ( HIST1H4C , HIST1H4D , HIST1H4E , HIST1H4F , HIST1H4I , HIST1H4J ) in 33 individuals total, all presenting with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, but with variable non-neurological features. Ten amino acids were affected, six of which were found recurrently. These mutations were located within either

9240-439: The context of chromatin. They contain a bromodomain , which helps them recognize and bind to acetylated lysine residues on histone substrates. Gcn5, p300/CBP , and TAF II 250 are some examples of type A HATs that cooperate with activators to enhance transcription. Type B HATs are located in the cytoplasm and are responsible for acetylating newly synthesized histones prior to their assembly into nucleosomes . These HATs lack

9360-445: The context of multisubunit complexes, have been shown to acetylate specific lysine residues in histones. Gcn5 cannot acetylate nucleosomal histones in the absence of other protein factors. In the context of complexes like SAGA and ADA, however, Gcn5 is able to acetylate H3K14 among other sites within histones H2B, H3, and H4 (e.g., H3K9, H3K36, H4K8, H4K16). Both Gcn5 and PCAF have the strongest site preference for H3K14, either as

9480-536: The context of their cognate complexes, Sas2 (SAS) and Esa1 (NuA4) also carry out acetylation of H4K16, in particular in the telomere regions of chromosomes. Sas2 is also observed to acetylate H3K14 in vitro on free histones. Esa1 can also acetylate H3K14 in vitro on free histones as well as H2AK5, H4K5, H4K8, and H4K12 either in vitro or in vivo on nucleosomal histones. H2AK7 and H2BK16 are also observed to be acetylated by Esa1 in vivo . Notably, neither Sas2 nor Esa1 can acetylate nucleosomal histones in vitro as

9600-403: The early 1990s, histones were dismissed by most as inert packing material for eukaryotic nuclear DNA, a view based in part on the models of Mark Ptashne and others, who believed that transcription was activated by protein-DNA and protein-protein interactions on largely naked DNA templates, as is the case in bacteria. During the 1980s, Yahli Lorch and Roger Kornberg showed that a nucleosome on

9720-529: The equilibrium between acetylation and deacetylation has also been associated with the manifestation of certain cancers. If histone acetyltransferases are inhibited, then damaged DNA may not be repaired, eventually leading to cell death. Controlling the chromatin remodeling process within cancer cells may provide a novel drug target for cancer research. Attacking these enzymes within cancer cells could lead to increased apoptosis due to high accumulation of DNA damage. One such inhibitor of histone acetyltransferases

9840-498: The general transcription factors TFIIE and TFIIF . Other proteins include CIITA , Brm (chromatin remodeler), NF-κB (p65), TAL1/SCL , Beta2/NeuroD , C/EBPβ , IRF2 , IRF7 , YY1 , KLF13 , EVI1 , AME, ER81 , and the androgen receptor (AR) . PCAF has also been observed to acetylate c-MYC , GATA-2 , retinoblastoma (Rb) , Ku70 , and E1A adenovirus protein. It can also autoacetylate, which facilitates intramolecular interactions with its bromodomain that may be involved in

9960-429: The highly conserved motif A found among GNATs that facilitates acetyl-CoA binding. A cysteine-rich region located in the N terminus of the HAT domain of MYST proteins is involved in zinc binding, which is essential for HAT activity. Tip60 (Tat-interactive protein, 60 kDa) was the first human MYST family member to exhibit HAT activity. Sas3 found in yeast is a homolog of MOZ (monocytic leukemia zinc finger protein), which

10080-515: The histone binding groove in the central core by moving the C-terminal segment of Gcn5 outward. In addition, since contacts between CoA and protein facilitate the formation of favorable histone-protein contacts, it is likely that CoA binding precedes histone binding in vivo . HATs in the GNAT family are most notably characterized by an approximately 160-residue HAT domain and a C-terminal bromodomain, which binds to acetylated lysine residues. Those in

10200-416: The histone substrate in a manner analogous to the mechanism used by GNATs. When Esa1 is assembled in the piccolo NuA4 complex, it loses its dependence on the cysteine residue for catalysis, which suggests that the reaction may proceed via a ternary bi-bi mechanism when the enzyme is part of a physiologically relevant multiprotein complex. In human p300, Tyr1467 acts as a general acid and Trp1436 helps orient

10320-406: The histone substrate. A conserved glutamate residue (Glu173 in yeast Gcn5) activates a water molecule for removal of a proton from the amine group on lysine, which activates it for direct nucleophilic attack on the carbonyl carbon of enzyme-bound acetyl-CoA. After the reaction, the acetylated histone is released first followed by CoA. Studies of yeast Esa1 from the MYST family of HATs have revealed

10440-420: The histones H2A and H2B can also be modified. Combinations of modifications, known as histone marks , are thought to constitute a code, the so-called " histone code ". Histone modifications act in diverse biological processes such as gene regulation , DNA repair , chromosome condensation ( mitosis ) and spermatogenesis ( meiosis ). The common nomenclature of histone modifications is: So H3K4me1 denotes

10560-550: The human TAF II 250 and CLOCK coactivators have not been studied as extensively. TAF II 250 is one of the TBP-associated factor subunits of TFIID , and it shares a Gly-X-Gly pattern with Gcn5 that is important for HAT activity. CLOCK is a circadian rhythm master regulator that functions with BMAL1 to carry out its HAT activity. Three important nuclear receptor coactivators that display HAT activity are SRC-1 , ACTR , and TIF-2 . Human SRC-1 (steroid receptor coactivator-1)

10680-436: The imine group of arginines and attach a keto group, so that there is one less positive charge on the amino acid residue. This process has been involved in the activation of gene expression by making the modified histones less tightly bound to DNA and thus making the chromatin more accessible. PADs can also produce the opposite effect by removing or inhibiting mono-methylation of arginine residues on histones and thus antagonizing

10800-499: The increase in the rate of histone synthesis is due to the increase in processing of pre-mRNA to its mature form as well as decrease in mRNA degradation; this results in an increase of active mRNA for translation of histone proteins. The mechanism for mRNA activation has been found to be the removal of a segment of the 3' end of the mRNA strand, and is dependent on association with stem-loop binding protein ( SLBP ). SLBP also stabilizes histone mRNAs during S phase by blocking degradation by

10920-537: The large genomes of eukaryotes inside cell nuclei: the compacted molecule is 40,000 times shorter than an unpacked molecule. Histones undergo posttranslational modifications that alter their interaction with DNA and nuclear proteins. The H3 and H4 histones have long tails protruding from the nucleosome , which can be covalently modified at several places. Modifications of the tail include methylation , acetylation , phosphorylation , ubiquitination , SUMOylation , citrullination , and ADP-ribosylation. The core of

11040-516: The late 19th century and is derived from the German word "Histon" , a word itself of uncertain origin, perhaps from Ancient Greek ἵστημι (hístēmi, “make stand”) or ἱστός (histós, “loom”). In the early 1960s, before the types of histones were known and before histones were known to be highly conserved across taxonomically diverse organisms, James F. Bonner and his collaborators began a study of these proteins that were known to be tightly associated with

11160-418: The latter bind across a groove on the protein that is formed by the central core region at the base and is flanked on opposite sides by the variable N- and C-terminal segments that mediate the majority of the interactions with the substrate peptide. It is likely that these variable regions are at least in part responsible for the observed specificity of different HATs for various histone substrates. Members of

11280-451: The lysine in position 4 of histone 3 located at the promoters of the c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc). c-fos is well known to be important in addiction . The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction. The first step of chromatin structure duplication

11400-778: The main ones. These variants with a variety of covalent modifications on the N-terminal can be added to histones making possible different chromatin structures that are required for DNA function in higher eukaryotes. Potential modifications include methylation (mono-, di-, or tri-methylation) or acetylation on the tails. Histone methylation occurs on arginine, lysine and histidine amino acids residues. Mono-, di- or tri-methylation has been discovered on histone H2A, H3 and H4. Histone methylation has been associated with various cellular functions such as transcription, DNA replication, and DNA damage response including repair, heterochromatin formation, and somatic cell reprogramming. Among these biological functions, transcriptional repression and activation are

11520-991: The maintenance of euchromatin . Additional acetylations include K31ac and K79ac. H4S1p H4R3me2 H4K5ac H4K8ac H4K12ac H4K16ac H4K16adp H4K20me H4K31ac H4S47o-p H4K79ac H4K91ac H4K91ub Histone In biology , histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla . They act as spools around which DNA winds to create structural units called nucleosomes . Nucleosomes in turn are wrapped into 30- nanometer fibers that form tightly packed chromatin . Histones prevent DNA from becoming tangled and protect it from DNA damage . In addition, histones play important roles in gene regulation and DNA replication . Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length

11640-426: The molecular basis for how this actually occurs is still largely unknown. However, data suggests that associated subunits may contribute to catalysis at least in part by facilitating productive binding of the HAT complex to its native histone substrates. The MYST family of HATs, p300/CBP, and Rtt109 have all been shown to be regulated by autoacetylation. Human MOF as well as yeast Esa1 and Sas2 are autoacetylated at

11760-697: The monomethylation of the 4th residue (a lysine) from the start (i.e., the N-terminal ) of the H3 protein. A huge catalogue of histone modifications have been described, but a functional understanding of most is still lacking. Collectively, it is thought that histone modifications may underlie a histone code , whereby combinations of histone modifications have specific meanings. However, most functional data concerns individual prominent histone modifications that are biochemically amenable to detailed study. The addition of one, two, or many methyl groups to lysine has little effect on

11880-416: The most highly conserved eukaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and cow differ at only 2 out of the 102 positions. This evolutionary conservation suggests that the functions of histone proteins involve nearly all of their amino acids so that any change is deleterious to the cell. Most changes in histone sequences are lethal; the few that are not lethal cause changes in

12000-419: The most highly conserved proteins in eukaryotes, emphasizing their important role in the biology of the nucleus. In contrast mature sperm cells largely use protamines to package their genomic DNA, most likely because this allows them to achieve an even higher packaging ratio. There are some variant forms in some of the major classes. They share amino acid sequence homology and core structural similarity to

12120-420: The most studied. Studies have shown that H4R3 methylation by PRMT1 (a histone methyltransferase) appears to be essential in vivo for the establishment or maintenance of a wide range of “active” chromatin modifications. Also methylation of histone H4 by PRMT1 was sufficient to permit subsequent acetylation on the N-terminal tail. However, acetylation of H4 inhibits its methylation by PRMT1. Acetylation of histones

12240-441: The need to alter multiple lysines to have a significant effect on chromatin structure. The modification includes H3K27ac . Addition of a negatively charged phosphate group can lead to major changes in protein structure, leading to the well-characterised role of phosphorylation in controlling protein function. It is not clear what structural implications histone phosphorylation has, but histone phosphorylation has clear functions as

12360-425: The next cell generation. H3 and H4 histone proteins are the primary targets of HATs, but H2A and H2B are also acetylated in vivo . Lysines 9, 14, 18, and 23 of H3 and lysines 5, 8, 12, and 16 of H4 are all targeted for acetylation. Lysines 5, 12, 15, and 20 are acetylated on histone H2B, while only lysines 5 and 9 have been observed to be acetylated on histone H2A. With so many different sites for acetylation,

12480-453: The only eukaryotes that completely lack histones, but later studies showed that their DNA still encodes histone genes. Unlike the core histones, homologs of the lysine-rich linker histone (H1) proteins are found in bacteria, otherwise known as nucleoprotein HC1/HC2. It has been proposed that core histone proteins are evolutionarily related to the helical part of the extended AAA+ ATPase domain,

12600-656: The packing of chromatin. The level of packing of the DNA is important for gene transcription, since the transcriptional machinery must have access to the promoter in order for transcription to occur. Neutralization of charged lysine residues by HATs allows for the chromatin to decondense so that this machinery has access to the gene to be transcribed. However, acetylation is not always associated with enhanced transcriptional activity. For instance, acetylation of H4K12 has been associated with condensed and transcriptionally inactive chromatin. In addition, some histone modifications are associated with both enhanced and repressed activity, in

12720-403: The pattern of gene expression as well as other abnormalities. Histone H4 is a 102 to 135 amino acid protein which shares a structural motif , known as the histone fold , formed from three a-helices connected by two loops. Histone proteins H3 and H4 bind to form a H3-H4 dimer, two of these H3-H4 dimers combine to form a tetramer . This tetramer further combines with two H2a-H2b dimers to form

12840-598: The positive effect arginine methylation has on transcriptional activity. Addition of an acetyl group has a major chemical effect on lysine as it neutralises the positive charge. This reduces electrostatic attraction between the histone and the negatively charged DNA backbone, loosening the chromatin structure; highly acetylated histones form more accessible chromatin and tend to be associated with active transcription. Lysine acetylation appears to be less precise in meaning than methylation, in that histone acetyltransferases tend to act on more than one lysine; presumably this reflects

12960-417: The presence of a bromodomain, and they are found to acetylate lysine residues on histones H2B , H3 , and H4 . All members of the GNAT family are characterized by up to four conserved motifs (A-D) found within the catalytic HAT domain. This includes the most highly conserved motif A, which contains an Arg/Gln-X-X-Gly-X-Gly/Ala sequence that is important for acetyl-CoA recognition and binding. The C motif

13080-543: The presence of either Asf1 or Vps75. In addition to the core histones, certain HATs acetylate a number of other cellular proteins including transcriptional activators , basal transcription factors , structural proteins, polyamines , and proteins involved in nuclear import. Acetylation of these proteins can alter their ability to interact with their cognate DNA and/or protein substrates. The idea that acetylation can affect protein function in this manner has led to inquiry regarding

13200-430: The prevention of the spread of silent heterochromatin . Furthermore, H2A.Z has roles in chromatin for genome stability. Another H2A variant H2A.X is phosphorylated at S139 in regions around double-strand breaks and marks the region undergoing DNA repair . Histone H3.3 is associated with the body of actively transcribed genes. Histones act as spools around which DNA winds. This enables the compaction necessary to fit

13320-502: The reformation of nucleosomes and are required for DNA damage repair systems to function. HATs have been implicated as accessories to disease progression, specifically in neurodegenerative disorders. For instance, Huntington's disease is a disease that affects motor skills and mental abilities. The only known mutation that has been implicated in the disease is in the N-terminal region of the protein huntingtin (htt) . It has been reported that htt directly interacts with HATs and represses

13440-496: The regulation of its HAT activity. p300/CBP have many non-histone substrates, including the non-histone chromatin proteins HMG1 , HMG-N1/HMG14 , and HMG-I(Y), the transcriptional activators p53, c-Myb , GATA-1 , EKLF , TCF , and HIV Tat, the nuclear receptor coactivators ACTR, SRC-1, and TIF-2, and the general transcription factors TFIIE and TFIIF. Other substrates include the transcription factors Sp1, KLF5 , FOXO1 , MEF2C , SRY , GATA-4 , and HNF-6 , HMG-B2 , STAT3 ,

13560-472: The role of acetyltransferases in signal transduction pathways and whether an appropriate analogy to kinases and phosphorylation events can be made in this respect. PCAF and p300/CBP are the main HATs that have been observed to acetylate a number of non-histone proteins. For PCAF, these include the non-histone chromatin ( high-mobility group (HMG) ) proteins HMG-N2/HMG17 and HMG-I(Y) , the transcriptional activators p53 , MyoD , E2F(1-3) , and HIV Tat , and

13680-476: The strong interactions between the histone and DNA. Acetylation is also thought to perturb interactions between individual nucleosomes and act as interaction sites for other DNA-associated proteins. There can be different levels of histone acetylation as well as other types of modifications, allowing the cell to have control over the level of chromatin packing during different cellular events such as replication, transcription, recombination, and repair. Acetylation

13800-424: The structure of histones has been evolutionarily conserved, as any deleterious mutations would be severely maladaptive. All histones have a highly positively charged N-terminus with many lysine and arginine residues. Core histones are found in the nuclei of eukaryotic cells and in most Archaeal phyla, but not in bacteria . The unicellular algae known as dinoflagellates were previously thought to be

13920-501: The substrate specificity of HATs. In general, while recombinant HATs are able to acetylate free histones, HATs can acetylate nucleosomal histones only when they are in their respective in vivo HAT complexes. Some of the proteins that associate with HATs in these complexes function by targeting the HAT complex to nucleosomes at specific regions in the genome . For instance, it has been observed that HAT complexes (e.g. SAGA, NuA3) often use methylated histones as docking sites so that

14040-404: The target lysine residue of the histone substrate into the active site. These two residues are highly conserved within the p300/CBP HAT family and, unlike enzymes in the GNAT and MYST families, p300 does not employ a general base for catalysis. Rather, it is likely that members of the p300/CBP family use a Theorell-Chance (i.e., “hit-and-run”) acetyl transfer mechanism. Rtt109 is likely to employ

14160-405: The whole cell cycle. In mammals, genes encoding canonical histones are typically clustered along chromosomes in 4 different highly- conserved loci, lack introns and use a stem loop structure at the 3' end instead of a polyA tail . Genes encoding histone variants are usually not clustered, have introns and their mRNAs are regulated with polyA tails. Complex multicellular organisms typically have

14280-415: Was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol. Methamphetamine addiction occurs in about 0.2% of the US population. Chronic methamphetamine use causes methylation of

14400-586: Was no consensus on the number of kinds of histone and that no one knew how they would compare when isolated from different organisms. Bonner and his collaborators then developed methods to separate each type of histone, purified individual histones, compared amino acid compositions in the same histone from different organisms, and compared amino acid sequences  of the same histone from different organisms in collaboration with Emil Smith from UCLA. For example, they found Histone IV sequence to be highly conserved between peas and calf thymus. However, their work on

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