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Histone Acetyltransferase Pathway

Figure1. Histone Acetyltransferase pathway

Histone Acetyltransferase overview

The most basic repeating unit in chromatin is the nucleosome core granule, which contains 147 bp of DNA wrapped around the central histone octamer. The nucleosome is a packing arrangement that compresses a piece of DNA about 2 m long into a nucleus with only 10 μm diameter, and this is also a dynamic structure containing many cellular processes. For example, nucleosomes can be post-translationally modified by chromatin-modifying enzymes, and chromatin can also be mediated by chromatin-engineered enzymes. Post-translational modifications of histones include acetylation, phosphorylation, methylation, ubiquitination, and ADP-ribosylation, and often occur in unorganized histone tails. Histone acetylation is perhaps the earliest post-translational modification of research and is also closely related to gene activation. Histone acetylation occurs in a specific lysine residue in the N-terminal basic amino acid concentration region of the core histone, and the acetyl group of acetyl-CoA is transferred to NH+ of lysine to neutralize a positive charge. Histone acetylation levels are determined by both histone acetyltransferase and histone deacetylase. In the nucleus, histone acetylation and histone deacetylation processes are in dynamic equilibrium, precisely regulating gene transcription and expression.

Histone Acetyltransferase family

At present, there are two types of molecules that have been found to contain histone acetyltransferase (HAT) activity. One is found in the nucleus, binds to histones on chromatin and acetylates it, and transcription of genes and corresponding organisms effect are related; one type exists in the cytoplasm, involved in chromatin replication, and has nothing to do with gene transcription. All acetylases can modify free-form histones, but only a portion of them can acetylate histones in nucleosome structures. In general, H3 and H4 are more susceptible to acetylation than H2A and H2B, but CBP and p300 can modify all four histones. In addition, each acetylase-modified lysine residue is different, indicating that the functions of different acetylases are different. At present, it is increasingly clear that acetylases are mostly present by forming larger complexes in the nucleus. Here, we focus on several of these acetyltransferases and their complexes, SAGA complex and NuA4 complex. Studies have shown that Gcn5p alone can only acetylate free histones without acetylating nucleosome matrices under physiological conditions. In contrast, its SAGA complex acetylates histones and nucleosomes. Since Ada 2, Ada 3 and Gcn5p are derived from triploid complexes, if the Ada 2/Ada 3/Gcn5p complex can acetylate nucleosomes, the Ada2/Ada3/Gcn5p complex assay can determine the complex. The activity is enough for free histone and nucleosome histone acetyltransferase. This indicates that the Ada2/Ada3/Gcn5p complex sub-component summarizes the function of the SAGA acetyltransferase acetylated nucleosome. However, in contrast to SAGA, the Ada2/Ad a 3/Gcn5p complex may only play a role as a local, untargeted nucleosome acetylase. p300/CBP: p300 and CBP regulate the transcriptional coactivators of many transcription factors, both of which have very similar amino acid sequences and similar functions and are therefore commonly referred to as p300/CBP. p300/CBP does not bind DNA by itself but is attracted to the promoter site by interaction with sequence-specific activators, mediating transcriptional activation. Smad3 is a protein important for intracellular signaling of transforming growth factors, which is phosphorylated and translocated to the nucleus to stimulate transcription of a select set of genes of interest. The Smad3 acetylation site mediated by p300/CBP is present on Lys 37 in the MH2 domain, and it is well known that the regulation of transcriptional activity is very important. ACTR: ACTR is a nuclear receptor coactivator with HAT activity discovered by Louie et al. It has multiple functional domains that interact with nuclear receptors and can independently interact with p300/CBP and PCAF, respectively, to enhance the transcriptional activation of nuclear receptors. ACTR acetylates free histones H2B, H3, and H4, as well as acetylated H3 and H4 in nucleosomes. It has no homology with the above HAT and is a new HAT.

Histone Acetyltransferase pathway

  1. Histone Acetyltransferase pathway cascade
    The cell cycle is regulated by positive regulatory factors and negative regulatory factors. Negative regulatory factors are composed of cyclin-dependent kinase inhibitors (CDKI). By inhibiting the protein kinase activity of the cyclin, CDK or Cycin-CDKI complex, CDKI blocks the cell from G1 to S phase, leading to the cessation of the cell cycle and achieving complete and precise negative regulation of the cell cycle. Nan et al. considered that Mecp-2 and transcriptional co-repressor complexes (including mSin3, HDAC) are involved in chromatin structural changes and mediate transcriptional repression, suggesting that they may be related. Landa Diner and other studies have found that the underlying methylation type has a profound effect on histone acetylation and is also an important effector in the animal genome. Studies have shown that many methylated genes are subject to inhibition mechanisms that affect histone acetylation. Espada et al. also found that lysine 16 of histone H4, a human cellular rRNA gene lacking DNA methyltransferase, would lose DNA methylation and the level of acetylation of H4 would increase. They observed that SirT1, a NAD-dependent histone deacetylase, interacts with DNMT1. Cells lacking DNMT 1 exhibited extensive hypomethylation of CpG residues at the 5' end of the 28S and 18S regions of the rRNA gene. Concomitant with this demethylation type, there is also an increase in the acetylation of the lysine 16 residue of histone H4 in this region. Similar combinations of DNA methylation and histone acetylation have also been found in other genomic regions. Collectively, the experiments provide evidence that dynamic changes in histone modifications and DNA methylation in the upstream coding region containing the transcription initiation site are important for tissue-specific gene expression and overall gene silencing. Aberrantly silenced tumor suppressor genes can be revived by either alone or in combination with DNA methylation and HDAC inhibitors. This is an important acquired modification mechanism for the treatment of malignant tumors. Histone acetylation and transcriptional regulation: Gene transcription is a complex process involving multiple factors, and the specificity of transcriptional regulation is determined by transcription factors that bind to specific DNA sequences. When these transcription factors bind to DNA, they can recruit transcriptional coactivators that affect basic transcriptional machinery and chromatin structure, thereby affecting transcription. These transcriptional coactivators play an important role in integrating information from different transcription factors and ultimately determining the level of transcription. The eukaryotic transcription-related HATs currently found include Gcn5, p 300/CBP, TAFII 250, MYST, PCAF, and the like. p300/CBP, TAF II 250, PCAF, etc. can directly enzymatically acetylate core histones, leading to chromatin stretching and even temporary deletion of nucleosome local structure, providing space for RNA polymerase transcription initiation and RNA strand extension. Among them, p300/CBP can bind to a variety of transcription factors and become a bridge between gene transcription regulators in the nucleus, allowing extracellular signals in different channels to regulate gene transcription in the nucleus. Many transcription factors can also be acetylated by HAT to regulate their activity. The most typical is the tumor suppressor gene p53, which is acetylated by CBP to enhance the affinity between the protein and its regulatory elements, thus affecting gene transcription. Inoue et al. found that acetylation of lys-378 in the MH2 domain mediated by p300/CBP is very important for the regulation of transcriptional activity. If arginine is used instead of Lys 378, the transcriptional activity of GAL4-Smad 3c is reduced.
    Pathway regulation and clinical research
    Current research does show that histone acetylation and deacetylation are associated with tumors. There is some evidence that the HAT has a tumor suppressor function, and if HAT activity is absent, dysregulation may lead to cancer. Viral oncoproteins bind to p300/CBP, and this interaction may inactivate p300/CBP. Similarly, E1A binding also inactivates Rb tumor suppressors. p300/CBP may also directly affect the activity of acetylated tumor suppressor of P53 because acetylation of P53 increases its binding activity to DNA and trans-acting activity. Camp bell et al found that the histone acetyltransferase gene ep300 may act as a tumor suppressor gene, which is located in the chromosome 22 region, and there is a heterozygous loss in many cancer types. The germline mutation of EP300 can explain the etiology of some breast tumor families. Fu and other experiments found that NAD-dependent histone deacetylase (Sir2) plays an important role in the relationship between cell metabolism and gene silencing. The androgen receptor (AR) is a ligand-modulated nuclear receptor that regulates the proliferation, differentiation, and apoptosis of prostate cancer cells regulated by androgens. Repression of AR signaling induced by DHT in human Sirt 1 requires NAD-dependent histone deacetylase function and deacetylation of AR lysine residues mediated by Sirt1. Sirt1 inhibits the coactivator-induced interaction between the amino and carboxy termini of AR and blocks DHT-induced prostate cancer cell growth, which is a key determinant in the development and progression of human prostate cancer. In many cancers, the anti-apoptotic transcription factor NF-κB is activated and is an important factor for cytokine-mediated tumor proliferation and migration. Breast cancer metastasis suppressor (BRMS1) is a metastasis suppressor gene, and Liu et al found that BRMS 1 reduced the reactivation of RelA /P65 and improved the anti-apoptotic gene product regulated by NF-kβ expression. BRMS1 functions as a co-repressor and inhibits the transcriptional activity of RelA/P65 by promoting the deacetylation of lysine K300 on RelA /P65 by promoting the binding of HDAC1 to RelA / P65. Therefore, BRMS1 acts as a transcriptional co-repressor against the apoptotic gene and inhibits tumor metastasis. In recent years, an increasing number of HDAC inhibitors have been discovered and demonstrated that these inhibitors are capable of inducing growth arrest, differentiation or apoptosis in many cultured transformed cells. By inhibiting the activity of HDAC, HDAC inhibitors cause accumulation of acetylated histones in cells, increasing the expression levels of genes such as p21 and p53, inhibiting the proliferation of tumor cells, and inducing cell differentiation and/or apoptosis. A variety of HDAC inhibitors have entered the clinical trial phase, and it is reasonable to believe that HDAC inhibitors can be a class of antitumor drugs with broad application prospects.

References:

  1. Jamal J, Mustafa M R, Wong P F. Paeonol protects against premature senescence in endothelial cells by modulating Sirtuin 1 pathway. Journal of Ethnopharmacology. 2014, 154(2):428-436.
  2. Parthun M R. Histone Acetyltransferase 1: More than Just an Enzyme? BBA - Gene Regulatory Mechanisms. 2012, 1819(3-4):256-263.
  3. Carlson S, Glass K C. The MOZ histone acetyltransferase in epigenetic signaling and disease. Journal of Cellular Physiology. 2014, 229(11):1571–1574.
  4. Tafrova JI, Tafrov S T. Human histone acetyltransferase 1 (Hat1) acetylates lysine 5 of histone H2A in vivo. Molecular & Cellular Biochemistry. 2014, 392(1-2):259-272.
  5. Yang Y, Han X, Guan J, et al. Regulation and function of histone acetyltransferase MOF. Frontiers of Medicine. 2014, 8(1):79.

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