Skip to Main contentScienceDirectJournals BooksRegisterSign in Sign inRegisterJournals BooksHelpHistone H3Histone H3 is a moderately diverse histone class, with more than half of the known full-length sequences displaying >80% identity in their histone fold domains;From: Methods in Enzymology, 2003Related terms:AcetylationLysineChromatinMethylationEpigeneticsHistone DeacetylaseProteinDNAHistoneView all TopicsDownload as PDFSet alertAbout this pageImmunohistochemistry for the Diagnosis of Melanocytic ProliferationsAchim A. Jungbluth, Klaus J. Busam, in Pathology of Melanocytic Tumors, 2019PHH3.Histone H3 is phosphorylated in the late G2 and M phases of the cell cycle. IHC for PHH3 (phosphor-histone H3) has been advocated to use for mitotic counting because it facilitates recognition of cells in mitosis, and their distinction from \"pseudo-mitotic structures,” i.e., nuclei undergoing apoptosis or pyknosis resembling a mitotic figure.32 Since PHH3 stains cells already in the mitotic prophase, which cannot be recognized on a routine hematoxylin and eosin (H E)-stained section, mitotic counts obtained using IHC for PHH3 tend to be higher than those obtained from counting well-developed mitotic figures on routine sections. As for Ki-67, a dual stain with a melanocyte differentiation marker is recommended to ensure that only melanocytes in mitoses are counted and not inflammatory or other cells. PHH3 has gained in popularity for counting mitotic figures in response to the seventh edition of the AJCC melanoma staging system, which elevated the importance of the mitotic count, as it became a crucial parameter for the distinction of pT1a from pT1b stage melanomas. The subsequent increase in reported mitotic counts in thin melanomas contributed to a revised staging system (AJCC, 8th edition), in which mitotic figures are no longer needed for staging. Accordingly, there is limited need for using PHH3.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780323374576000298Intracellular Signalling ProteinsEmmanuel Valjent, ... Emma Puighermanal, in Advances in Protein Chemistry and Structural Biology, 20193.5 Histone H3 phosphorylation and regulation of transcription in the striatumHistone H3 phosphorylation is highly dynamic and participates to the regulation of chromatin remodeling necessary to trigger initiation and elongation of transcription of specific transcripts (Sawicka Seiser, 2012). In most of the aforementioned studies, histone H3 phosphorylation at S10, which occurs independently on preacetylated histone H3 has been associated with increased expression of immediate early genes including c-Fos (Bertran-Gonzalez et al., 2009; Brami-Cherrier et al., 2005; Kumar et al., 2005; Santini, Alcacer, et al., 2009; Santini et al., 2007). Importantly, chromatin immunoprecipitation assays demonstrated that pS10acK14-H3 occurs directly at the c-fos and fosB promoters in striatal neurons in response to cocaine and l-DOPA, respectively (Feyder et al., 2016; Jordi et al., 2013; Kumar et al., 2005). Although the demonstration per se of a direct causal link between these two events will be difficult to establish, evidence indicates that blockade of pS10-H3 phosphorylation is associated with altered nucleosomal responses. Thus, the decrease of pS10-H3 and pS10acK14-H3 observed in MSK1-deficient mice or following inhibition of Elk-1 phosphorylation in response to cocaine or l-DOPA is accompanied by reduced expression of several genes including c-fos, zif268, ΔFosB and Arc/Arg3.1 in striatal SPNs (Alcacer et al., 2014; Besnard et al., 2011; Brami-Cherrier et al., 2005; Feyder et al., 2016). Lastly, the increased S28me3K27-H3 phosphorylation induced by l-DOPA, d-amphetamine or haloperidol has been shown to correlate with reduced binding of polycomb group complexes leading to derepression and eventually increased transcription of a subset of genes in D1R- and D2R-SPNs including Atf3, Npas4, Klf4 and Lipg (Bonito-Oliva et al., 2016; Sodersten et al., 2014). It is likely that chromatin immunoprecipitation followed by RNA sequencing will allow the identification of new subsets of genes whose expression or repression are tightly linked to the state of histone H3 phosphorylation at S10 and S28, respectively.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/S1876162319300148Protein-Protein Interactions in Human Disease, Part ABárbara I. Díaz-Eufracio, ... José L. Medina-Franco, in Advances in Protein Chemistry and Structural Biology, 20182.6 Histone Methyltransferases (HMTs)Histone 3 lysine 4- and histone 3 lysine 36 (H3K4 and H3K36, respectively) methylation regulate diverse processes implicated in cancer, including transcriptional regulation, alternative splicing, and DNA repair. SMYD2 is a protooncogene methyltransferase that represses the functional activity of the tumor suppressor protein p53 (Huang et al., 2006).Cowen et al. designed substrate competitive SMYD2 inhibitors. Authors concluded that perhaps the most interesting feature of the binding mode of the synthetic compound AZ505 (Fig. 1), is that the dichlorophenethyl moiety of the inhibitor extends across the peptide-binding groove of SMYD2 and is inserted into a secondary hydrophobic pocket adjacent to the cofactor binding site (Cowen et al., 2016).Among other HMTs inhibitors, A-893 was found to function as a peptide-competitive inhibitor (Sweis et al., 2015). BIX-01294 is a very interesting compound acting through occupying the binding pocket of histones in HMTs (Di Costanzo, Del Gaudio, Migliaccio, Altucci, 2014). In turn, EPZ-5676 (Fig. 1) is a DOT1L inhibitor undergoing clinical trials for its use in leukemia (Abdel-Wahab Levine, 2013). Remarkably, DOT1L interacts with fusion proteins including MLL, in a variety of leukemias (Campbell Tummino, 2014).EZH2, a HMT that forms part of Polycomb repressive complex 2, regulates cell differentiation and homeostasis. Its hyperactivity has been linked to tumor suppression genes repression and carcinogenesis. Besides direct enzymatic inhibition, its critical PPI with EED (a methyl-lysine reader) have been targeted through peptides, with antineoplastic results (Kim et al., 2013). Similarly to EED, BHC80, an unmethylated lysines reader, has been found to be important in LSD1 function as a HMT (Lan et al., 2007).View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/S1876162317300421Chromatin modification and remodeling in schizophreniaJubao Duan, in Chromatin Signaling and Neurological Disorders, 201914.4.1 Histone acetylationHistone H3 is primarily acetylated at lysine (K) residues positions K9, K14, K18, K23, K27, and K56. Histone acetylation and deacetylation are modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Histone acetylation by HATs is often associated with a more open chromatin and active transcription, while histone deacetylation by HDACs often leads to a more condensed chromatin and repressive transcription. Acetylation of histone H3 at lysine 27 (H3K27ac) together with H3K64ac and H3K122ac, and an H4 tail acetylation, H4K16ac, are enriched at active enhancers [41]. The role of histone acetylation and deacetylation in SZ has been interrogated in both peripheral blood cells and in postmortem brains.Earlier studies of histone acetylation in SZ were performed in blood cells, aiming to identify possible biomarkers that can be easily implemented for clinical diagnosis. An initial study with very small number of SZ and bipolar patients (n = 14) were treated with a clinically proven drug, valproic acid (VA), which is also a potent inhibitor of HDACs [42]. The acetylated histones H3 and H4 in SZ lymphocytes were found to be irresponsive to VA treatment [42]. The baseline levels of H3 K9/K14 acetylation in SZ blood cells were also found to be lower (measured by Western blot) than in controls [43]. Consistent with the result from blood cells, later study of postmortem brain histone H3 K9/K14 was found to be hypoacetylated (measured by chromatin immunoprecipitation-qPCR) at the promoter regions of several SZ candidate genes, including GAD1, 5-hydroxytryptamine (serotonin) receptor 2C, and the myelin-related genes in SZ [44]. These studies, although very few, suggest that the reduced H3 K9/K14 acetylation might be associated with SZ.The association of histone acetylation changes with SZ in the brain has not been systematically examined. However, genome-wide histone acetylation study on autism (ASD) may provide some insights on SZ, give that both are neurodevelopmental disorders that partially share molecular neuropathology [45]. A H3K27ac (active enhancers) chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem brain samples from ASD patients and matched controls identified a common acetylome signature for 5000 cis-regulatory elements in the prefrontal and temporal cortex [46]. By further correlating histone acetylation with genotypes, the authors discovered 2000 brain histone acetylation quantitative trait loci (haQTLs), some of which overlap with putative causal variants for SZ and ASD (e.g., rs4765905 in CACNA1 and rs8054791 in GRIN2A) [46]. It is noteworthy that ∼77% of the binding sites of TCF4, a transcription factor encoded by a leading SZ GWAS risk gene, overlap with the H3K27ac histone modification [47].In addition to possible aberrant histone acetylation in SZ, abnormal expression for enzymes that modulate histone acetylation or deacetylation, mainly HDACs, has also been implicated in SZ. In a study with a large well-characterized human postmortem brain sample (n = 700), the transcripts of HDAC2, but not HDAC1, in SZ-relevant adult DLPFC were decreased by 34% in SZ compared to controls [48]. Although this interesting observation may be confounded by use of antipsychotic drugs or other environmental factors, it was noted that neither smoking nor therapeutic drugs impacted HDAC2 levels [48]. However, the observed reduction of HDAC2 expression in SZ postmortem brains was not replicated by some other studies. In one study, HDAC1 levels were found to be increased in blood samples of SZ patients who had encountered early-life stress (ELS), compared to patients without ELS [49]. In another study, the hippocampus of SZ-like mice showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3 [50]. Therefore, it remains unclear which types of HDACs are relevant to SZ, and how they may impair the SZ phenotypes. More systematic study of HDACs in SZ is needed, which may implicate other HDACs, such as HDAC9 (see later section), in SZ pathogenesis.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128137963000146Oocyte Meiotic MaturationHeng-Yu Fan, Qing-Yuan Sun, in The Ovary (Third Edition), 2019Histone H3 Lysine-4 TrimethylationHistone H3 lysine-4 trimethylation (H3K4me3) is a type of histone modifications that associates with eukaryotic gene promoters and poises them for development- or environment-triggered transcriptional activation. The H3K4me3 level was low in growing NSN oocytes (Fig. 9C and E), but was significantly increased in fully grown SN oocytes (Fig. 9D and F), suggesting that H3K4me3 accumulation is an important aspect of oocyte epigenetic maturation. After ovulation, H3K4me3 localized to the condensed chromosomes in metaphase II (MII)-arrested oocytes, and was inherited by the female pronucleus after fertilization.In mammalian cells, H3K4 trimethylation is mediated mainly by the SETD1 complex and mixed-lineage leukemia (MLL) family of proteins [89]. CXXC finger protein-1 (CFP1), encoded by the Cxxc1 gene in mice, is a key component of the eukaryotic SETD1 complex [90,91]. CFP1 binds with DNA using its CXXC finger domain and recruits SETD1 to specific genome regions [92]. In mammalian oocytes, trimethylation of histone H3 at lysine-4 is mainly mediated by SETD1-CFP1 and MLL2. The H3K4me3 level was remarkably decreased, but not completely abolished, in MLL2- or CFP1-deleted oocytes. CFP1 deletion affected the expression of a wide range of maternal genes, disregarding their original expression abundances. Similar to CFP1 deletion, MLL2 deletion in oocytes led to female infertility [93]. In contrast to H3K4me3, the H3K4me1 and H3K4me2 levels were not affected by CFP1 deletion, but were downregulated in MLL2-deleted oocytes [93]. Therefore, MLL2 may primarily be responsible for maternal H3K4me2 accumulation and indirectly affects H3K4me3 in oocytes, whereas the CFP1-SETD1 complex is the major methyltransferase that directly generates H3K4me3 during oogenesis.A balanced H3K4 methylation status is essential not only for maintaining transcription in the growing oocyte, but also for triggering zygotic genome activation (ZGA) (Fig. 10). Histone H3K4me3 is enriched in the female pronucleus after fertilization and is only start to be detected in the male pronucleus at the late zygotic stage [94]. In developing oocytes and zygotes, MLL2, MLL3, and MLL4 were being reported to contribute to H3K4 methylation [93,95], whereas KDM1A (lysine demethylase), KDM1B, and KDM5B were reported to demethylate H3K4 [96,97]. Deletion of these KDMs caused defects in oogenesis and ZGA [98–101]. H3K4me3 deposits gene promoters as broad peaks on oocyte genome, but is promptly removed by KDMs after fertilization. As a result, only narrow and sharp H3K4me3 peaks remained on the genome of two- to four-cell embryos. This large-scale H3K4me3 removal from maternal genome is necessary for successful ZGA.Fig. 10. Summary of CFP1 function related to epigenetic regulation in oocyte development and zygotic genome activation. By facilitating histone H3K4 trimethylation and histone exchange in oocytes, CFP1 maintains the expression of key oocyte genes, including those encoding for DNA methyltransferases (DNMTs), cytoplasmic lattice (CPL) components, MZT licensing factor BTG4, and DNA demethylase TET3. These CFP1 regulated factors are involved in the establishment of maternal genome imprinting and cytoplasmic organelle distribution during oocyte maturation, as well as maternal transcript clearance and DNA demethylation after fertilization. Furthermore, maternal CFP1 ensure prompt histone deposition and zygotic genome activation in 1–2-cell embryos.Although the removal of bulk H3K4me3 from zygotic chromatin is a key step that leads to ZGA, the proper deposition of H3K4me3 at the promoters of certain important zygotic genes (as narrow peaks) are also required. Despite, results of this study and other reports indicated that insufficient maternal H3K4me3 accumulation also caused failure of preimplantation embryonic development: maternal Mll2 knockout embryos arrest at the two-cell stage [93]; inhibition of histone H3K4 methytransferase activity by overexpressing a dominant negative histone H3 mutant (K4-to-M mutation) in oocytes also blocked ZGA and impaired embryonic development [95]. Collectively, these results suggest that the balanced H3K4 modification mediated by both CFP1 and KDMs is crucial for the acquisition of oocyte competence.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128132098000121Primary Sjögren’s Syndrome and EpigeneticsAmandine Charras, ... Yves Renaudineau, in The Epigenetics of Autoimmunity, 201811.6 Histones in pSSGlobal histone H3 and H4 hyperacetylation, and histone H3 demethylation, at lysine 4 characterize CD4+ T cells from SLE patients [87]. In addition to positively affecting transcription, these modifications can also lead to the development of specific auto-Ab. This was demonstrated with the lupus-derived monoclonal Ab BT-164 and KM-2, which recognize histone H3 trimethylated lysine 27 and histone H4 acetylated lysine 8, 12, and 16, respectively [88–90]. Blocking histone hyperacetylation represents an interesting therapeutic alternative as two histone deacetylase inhibitors (Trichostatin A and suberoylanilide hydroxamic acid) can revert histone modifications and improve SLE symptoms in mice without affecting auto-Ab titers [91,92]. These results provide arguments to suggest that the DNA methylation modifications that characterize pSS patients are associated with histone modifications, and that some of the antihistone auto-Abs detected in pSS target posttranslational histone modifications [93]. TNFα inhibition of AQP5 expression in the NS-SV-AC cell line was tested, and demonstrated that such inhibition was independent of DNA methylation but controlled by histone H4 acetylation [56].View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128099124000118EpigeneticsDavid P. Gavin, Christina Floreani, in International Review of Neurobiology, 20144.1 Relaxing histone modificationsHistone 3 serine 10 phosphorylation (H3S10ph) is catalyzed by a variety of kinases including Aurora kinases, as well as enzymes downstream from serotonin receptors, such as protein kinase C (PKC), and dopamine receptors, such as protein kinase A (Huang, Mishra, Batra, Dillon, Mehta, 2004; Li et al., 2004). The mitogen-associated protein kinase pathway can also lead to H3S10ph (Drobic, Perez-Cadahia, Yu, Kung, Davie, 2010).H3S10ph serves to displace the H3K9me3 binding protein, HP1 (Hirota, Lipp, Toh, Peters, 2005). Once HP1 is removed, the underlying histone methyl groups are accessible to histone demethylases. JMJD1A, JMJD1B, and LSD1 demethylate mono- and dimethylated H3K9, while JMJD2A, JMJD2B, and JMJD2C demethylate di- or trimethylated H3K9 (Lim, Metzger, Schule, Kirfel, Buettner, 2010). H3S10ph has also been shown to facilitate lysine acetylation (Agalioti, Chen, Thanos, 2002; Cheung et al., 2000). H3 lysine acetylation is catalyzed by histone acetyltransferase enzymes (HATs) (Agalioti et al., 2002; Strahl Allis, 2000). Finally, H3K4 methylation is catalyzed by MLL1–4, SET1A, and SET1B (Herz, Garruss, Shilatifard, 2013) and serves to immunize the promoter region from rapidly being silenced again as DNMTs are incapable of binding regions with trimethylated H3K4 (Ciccone et al., 2009; Nan et al., 1998; Ooi et al., 2007).View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128013113000056Role of Histone Modifications in Chronic Pain DevelopmentJixiang Zhang, Hui-Lin Pan, in Epigenetics of Chronic Pain, 2019H3K27me3Histone H3 lysine 27 trimethylation (H3K27me3) helps to maintain the repressed state of critical genes during development (Fig. 1). In mammals, H3K27me3 is dynamically deposited by polycomb repressive complex 2 (PRC2), the polycomb group (PcG) proteins (Cao et al., 2002). The PcG proteins were identified in Drosophila as silencers of the Hox genes. Mutations in PcG lead to ectopic expression of key developmental regulators in flies, resulting in body patterning defects (Cao and Zhang, 2004; Kennison, 1995; Schuettengruber et al., 2007). The core PRC2 complex is composed of multiple subunits, including enhancer of zeste (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12), as well as RBBP4 (RbAp48) and RBBP7 (RbAp46) (Cao et al., 2002). EZH2 is the catalytic subunits of PRC2, acting as the methyltransferase of H3K27. H3K27me3 could be removed by lysine demethylase 6A (KDM6a) and KDM6b (also known as JMJD3), two Jumonji domain-containing histone demethylases (Agger et al., 2007; Lan et al., 2007).EZH2 plays a major role in cancer, X-chromosome inactivation, stem cell identity, and regeneration (Conway et al., 2015; Grossniklaus and Paro, 2014). It also facilitates the formation of long-range chromosome topologically associating domains during cell proliferation and differentiation (Cheutin and Cavalli, 2014). EZH2 is expressed in DRG neurons, and nerve injury increases the EZH2 expression level in the DRG (Laumet et al., 2015). EZH2 is involved in the repression of Kcnd2, Kcnq2, and Kcnma1 after nerve injury. However, the EZH2 inhibitor GSK503 has a small effect in reversing SNL-induced pain hypersensitivity (Laumet et al., 2015). EZH2 is also upregulated in the spinal dorsal horn after nerve injury (Yadav and Weng, 2017). The high level of H3K27me3 seems to correlate with glial activation in neuropathic pain (Yadav and Weng, 2017).View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128140703000041Advances in Cancer ResearchLiliya Tyutyunyk-Massey, ... Joseph W. Landry, in Advances in Cancer Research, 20182.2.2 Histone DemethylasesThe histone 3 K27 demethylase KDM6B is overexpressed in a germinal center B-cell subtype of DLBCL, and higher KDM6B expression levels associate with worse survival from the disease. Inhibition of KDM6B in DLBCL using the small-molecule inhibitor GSK-J4 induced apoptosis in several cell line models of DLBCL which includes SU-DHL-6, OCI-Ly1, Toledo, OCI-Ly8, and SU-DHL-8. GSK-J4 treatment resulted in downregulation of B-cell receptor (BCR) signaling and a downstream BCR target gene, BCL6. BCL6 is a transcription repressor which acts as an oncogene in germinal center-derived lymphomas such as DLBCL (Basso Dalla-Favera, 2012). Relevant to this review, GSK-J4 treatments resulted in sensitization to doxorubicin as measured by increased apoptosis (Mathur et al., 2017).View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/S0065230X18300101Molecular Mechanisms of MemoryJ.M. Levenson, M.A. Wood, in Learning and Memory: A Comprehensive Reference, 20084.42.2.6 Histone PhosphorylationPhosphorylation of histones H1 and H3 was first discovered in the context of chromosome condensation during mitosis (Bradbury et al., 1973; Gurley et al., 1974). Phosphorylation of histone H3 has since been associated with activation of mitogenic signaling pathways (Mahadevan et al., 1991). Phosphorylation of serine 10 on H3 is mediated by Rsk2, Msk1, and the aurora kinase family member Ipl1 (Sassone-Corsi et al., 1999; Thomson et al., 1999; Hsu et al., 2000; Di Agostino et al., 2002). Recent evidence also implicates aurora kinases in the phosphorylation of serine 28 in histone H3 (Goto et al., 2002). As with other proteins, phosphatases are responsible for catalyzing the removal of phosphate groups from histones (Mahadevan et al., 1991; Ajiro et al., 1996). To date, the phosphatases PP1 and PP2A have been shown to regulate levels of phosphorylation on H3 (Hsu et al., 2000; Nowak et al., 2003).View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123705099000437Recommended publicationsInfo iconDevelopmental BiologyJournalBrain ResearchJournalCellJournalNeuronJournalBrowse books and journalsAbout ScienceDirectRemote accessShopping cartAdvertiseContact and supportTerms and conditionsPrivacy policyWe use cookies to help provide and enhance our service and tailor content and ads. By continuing you agree to the use of cookies.Copyright © 2021 Elsevier B.V. or its licensors or contributors. 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