99-66-1NIJJYAXOARWZEE-UHFFFAOYSA-NNIJJYAXOARWZEE-UHFFFAOYSA-N
Valproic acidVPA
Pentanoic acid, 2-propyl-
2-Propylpentanoic acid
2-Propylvaleriansaure
2-propylvaleric acid
4-Heptanecarboxylic acid
Acetic acid, dipropyl-
acide 2-propylvalerique
acido 2-propilvalerico
Depakine
Dipropylacetic acid
Ergenyl
Mylproin
n-Dipropylacetic acid
NSC 93819
VALERIC ACID, 2-PROPYL-
DTXSID6023733461-55-2FERIUCNNQQJTOY-UHFFFAOYSA-MFERIUCNNQQJTOY-UHFFFAOYSA-M
ButyrateDTXSID804043258880-19-6RTKIYFITIVXBLE-QEQCGCAPSA-NRTKIYFITIVXBLE-QEQCGCAPSA-N
Trichostatin ATSA
DTXSID6037063149647-78-9WAEXFXRVDQXREF-UHFFFAOYSA-NWAEXFXRVDQXREF-UHFFFAOYSA-N
Suberoylanilide hydroxamic acidvorinostat
Octanediamide, N-hydroxy-N'-phenyl-
SAHA
DTXSID6041133209783-80-2INVTYAOGFAGBOE-UHFFFAOYSA-NINVTYAOGFAGBOE-UHFFFAOYSA-N
MS-275DTXSID0041068183506-66-3JWOGUUIOCYMBPV-GMFLJSBRSA-NJWOGUUIOCYMBPV-LQJYRIKDSA-N
Apicidin(3S,6S,9S,15aR)-9-[(2S)-Butan-2-yl]-6-[(1-methoxy-1H-indol-3-yl)methyl]-3-(6-oxooctyl)octahydro-2H-pyrido[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10(3H,12H)-tetrone
Apicidin Ia
DTXSID40274182625-45-6RMIODHQZRUFFFF-UHFFFAOYSA-NRMIODHQZRUFFFF-UHFFFAOYSA-N
Methoxyacetic acidAcetic acid, methoxy-
2-Methoxyacetic acid
ACETIC ACID, METHOXY
Acide methoxyacetique
acido metoxiacetico
Methoxy acetic acid
Methoxyessigsaure
Methoxyethanoic acid
NSC 7300
DTXSID1031591PR:000008478histone deacetylase 1GO:0004857enzyme inhibitor activity2decreasedValproic acid2018-12-20T04:35:212018-12-20T04:35:21Butyrate2018-01-21T20:39:192018-01-21T20:39:19Trichostatin A2018-01-21T20:39:332018-01-21T20:39:33Suberoylanilide hydroxamic acid2018-12-20T04:36:362018-12-20T04:36:36MS-2752018-12-20T04:37:022018-12-20T04:37:02Apicidin2018-12-20T04:37:152018-12-20T04:37:15Methoxyacetic acid2018-01-21T20:38:502018-01-21T20:38:50Rocilinostat / Ricolinostat2021-06-23T05:53:112021-06-23T05:53:1110116ratWCS_9606human10090mouseHistone deacetylase inhibitionHistone deacetylase inhibitionMolecular<p>Nucleosomes consist of eight core histones, two of each histone H2A, H2B, H3, and H4 [Damaskos et al., 2017]. DNA strands (about 200 bp) wind around the core histones, which can be modified on their N-terminal ends. One possible modification is the acetylation of lysine residues, which decreases the binding strength between DNA and the core histone. Histone deacetylases (HDACs) hydrolyze the acetyl residues [Damaskos et al., 2017]. HDACs remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Thus, the inhibition of HDAC blocks this action and can result in hyperacetylation of histones associated mostly with increases in transcriptional activation. Histone deacetylase inhibitor (HDI) inhibits HDAC, causing increased acetylation of the histones and thereby facilitating binding of transcription factors [Taunton et al., 1996].</p>
<p>It is known that eukaryotic HDAC isoforms are classified into four classes: class I HDACs (isoforms 1, 2, 3, 8), class II HDACs (isoforms 4, 5, 6, 7, 9, 10), class III HDACs (the sirtuins), and HDAC11 [Gregoretti et al., 2004; Weichert, 2009; Barneda-Zahonero and Parra, 2012]. HDACs 1, 2, and 3 are ubiquitously expressed, whereas HDAC8 is predominantly expressed in cells with smooth muscle/myoepithelial differentiation [Weichert, 2009]. HDAC6 is not observed to be expressed in lymphocytes, stromal cells, and vascular endothelial cells [Weichert, 2009]. Class III HDACs, sirtuins, are widely expressed and localized in different cellular compartments [Barneda-Zahonero and Parra, 2012]. SirT1 is highly expressed in testis, thymus, and multiple types of germ cells [Bell et al., 2014]. HDAC11 expression is enriched in the kidney, brain, testis, heart, and skeletal muscle [Barneda-Zahonero and Parra, 2012]. The members of classes 1, 2, and 4 are dependent on a zinc ion and a water molecule at their active sites, for their deacetylase function. The Sirtuins of class 3 depend on NAD<sup>+</sup> and are considered impervious to most known HDAC inhibitors [Drummond et al., 2005].</p>
<p>Several structurally distinct groups of compounds have been found to inhibit HDACs of class 1, 2, and 4, among others short-chain fatty acids (e.g. butyrate and VPA), hydroxamic acids (e.g. TSA and SAHA), and epoxyketones (e.g. Trapoxin) [Drummond et al., 2005]. The hydroxamic acids seem to exert their inhibitory action by mimicking the acetyl-lysine target of HDACs, chelating the zinc ion in the active site, and displacing the water molecule [Finnin et al., 1999]. Several high-resolution crystal structures support this mode of inhibition [Decroos et al., 2015; Luckhurst et al., 2016]. The mode of inhibition of epoxyketones seems to function in the formation of a stable transition state analog with the zinc ion in the active site [Porter and Christianson, 2017]. The inhibitory actions of the short-chain fatty acids are less well defined, but it has been speculated that VPA blocks access to the binding pocket [Göttlicher et al., 2001]. It has been shown that VPA exerts similar gene regulatory effects to TSA, on a panel of migration-related transcripts in neural crest cells [Dreser et al., 2015], supporting a mode of action similar to hydroxamic-acid type HDAC inhibitors. Some <em>in silico</em> methods including molecular modeling, virtual screening, and molecular dynamics are used to find the common HDAC inhibitor structures [Huang et al., 2016; Yanuar et al. 2016].</p>
<p>The measurement of HDAC inhibition monitors changes in histone acetylation. HDAC inhibition can be detected directly by the measurement of HDAC activity using commercially available colorimetric or fluorimetric kits or indirectly by the increase of histone acetylation as the detection of global histone acetylation changes by Western blot or mass spectrometry (MS)-based proteomics methods or as detection of site-specific histone acetylation changes using chromatin immunoprecipitation (ChIP) or ChIP-on-Chip. The measurement methods include the immunological detection of histone acetylation with anti-acetylated histone antibodies [Richon et al., 2004]. The histones are isolated from pellets of cells treated with HDIs, followed by acid-urea-triton gel electrophoresis, western blotting, and immunohistochemistry [Richon et al., 2003]. The HDAC activity is measured directly with ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) by calculating the ratio of deacetylated peptide and acetylated peptide [Zwick et al., 2016]. <span style="color:#2980b9">HDAC inhibition can be predicted by perturbations in gene expression patterns as well; an 81-gene transcriptomic biomarker of HDAC inhibition, called TGx-HDACi, has shown to accurately predict HDAC inhibition after 4 hour exposures to HDI in TK6 human lymphoblastoid cells [Cho et al., 2021]. </span> </p>
<p>The inhibition of HDAC by HDIs is well conserved between species from lower organisms to mammals.</p>
<ul>
<li>HDAC inhibition restores the rate of resorption of subretinal blebs in hyperglycemia in brown Norway rat and HDAC activity was inhibited with HDIs in human ARPE19 cells [Desjardins et al., 2016].</li>
<li>Treatment of HDIs inducing HDAC inhibition showed anti-tumor effects in human non-small cell lung cancer cells [Ansari et al., 2016; Miyanaga et al., 2008].</li>
<li>HDAC acetylation level was increased by HDIs in the MRL-lpr/lpr murine model of lupus splenocytes [Mishra et al., 2003].</li>
<li>SAHA increased histone acetylation in the brain and spleen of mice [Hockly et al., 2003].</li>
<li>MAA inhibits HDAC activity in HeLa cells and spleens from C57BL/6 mice [Jansen et al., 2004].</li>
<li>It is also reported that MAA inhibits HDAC activity in testis cytosolic and nuclear extract of juvenile rats (27 days old) [Wade et al., 2008].</li>
<li>VPA and TSA inhibit HDAC enzymatic activity in the mouse embryo and human HeLa cell nuclear extract [Di Renzo et al., 2007].</li>
<li>The treatment with HDAC inhibitors, phenylbutyrate (PB) (2 mM) and TSA (200 nM), inhibits HDAC in adjuvant arthritis synovial cells derived from rats, causing higher acetylated histone [Chung et al., 2003].</li>
</ul>
UBERON:0000062organCL:0000000cellHighUnspecificModerateAll life stagesHighHighHigh<p>Ansari, J. et al. (2016), "Epigenetics in non-small cell lung cancer: from basics to therapeutics", Transl Lung Cancer Res 5:155-171</p>
<p>Barneda-Zahonero, B. and Parra, M. (2012), "Histone deacetylases and cancer", Mol Oncol 6:579-589</p>
<p>Bell, E.L. et al. (2014), "SirT1 is required in the male germ cell for differentiation and fecundity in mice", Development 141:3495-3504</p>
<p><span style="color:#2980b9">Cho, E. et al. (2021), "Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells", Arch Toxicol 95:1631–1645</span></p>
<p>Chung, Y.L. et al. (2003), "A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis", Mol Ther 8:707-717</p>
<p>Damaskos, C. et al. (2016), "Histone deacetylase inhibitors: a novel therapeutic weapon against medullary thyroid cancer?", Anticancer Res 36:5019-5024</p>
<p>Damaskos, C. et al. (2017), "Histone deacetylase inhibitors: an attractive therapeutic strategy against breast cancer", Anticancer Research 37:35-46</p>
<p>Decroos, C. et al. (2015), "Biochemical and structural characterization of HDAC8 mutants associated with cornelia de lange syndrome spectrum disorders", Biochemistry 54:6501–6513</p>
<p>Desjardins, D. et al. (2016), "Histone deacetylase inhibition restores retinal pigment epithelium function in hyperglycemia", PLoS ONE 11:e0162596</p>
<p>Di Renzo, F. et al. (2007), "Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity", Toxicol and Appl Pharmacol 220:178-185</p>
<p>Dreser, N. et al. (2015), "Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling", Neurotoxicology 50:56–70</p>
<p>Drummond, D.C. et al. (2005), "Clinical development of histone deacetylase inhibitors as anticancer agents", Annu Rev Pharmacol Toxicol 45:495–528</p>
<p>Finnin, M.S. et al. (1999), "Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors", Nature 401:188–193</p>
<p>Göttlicher, M. et al. (2001), "Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells", EMBO J 20:6969–6978</p>
<p>Gregoretti, I.V. et al. (2004), "Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis", J Mol Biol 338:17–31</p>
<p>Hockly, E. et al. (2003), "Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease", Proc Nat Acad Sci 100:2041-2046</p>
<p>Hu, E. et al. (2003), "Identification of novel isoform-selective inhibitors within class I histone deacetylases", J Pharmacol Exp Ther 307:720-728</p>
<p>Huang, Y.X. et al. (2016), "Virtual screening and experimental validation of novel histone deacetylase inhibitors", BMC Pharmacol Toxicol 17(1):32</p>
<p>Jansen, M.S. et al. (2014), "Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition", Proc Natl Acad Sci USA 101(18):7199-7204</p>
<p>Luckhurst, C.A. et al. (2016), "Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors", ACS Med Chem Lett 7:34–39</p>
<p>Mishra, N. et al. (2003), "Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse", J Clin Invest 111:539-552</p>
<p>Miyanaga, A. et al. (2008), "Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model", Mol Cancer Ther 7:1923-1930</p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px">Ooi, J.Y.Y., et al. (2015), “HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes”, Epigenetics 10:418-430</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Park M.J. and Sohrabi F. (2016), “The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats”, J Neuroinflammation 13:300</span></span></p>
<p>Porter, N.J., and Christianson, D.W. (2017), "Binding of the microbial cyclic tetrapeptide trapoxin A to the Class I histone deacetylase HDAC8", ACS Chem Biol 12:2281–2286</p>
<p>Richon, V.M. et al. (2003), "Histone deacetylase inhibitors: assays to assess effectiveness in vitro and in vivo", Methods Enzymol. 376:199-205</p>
<p>Ropero, S. and Esteller, M. (2007), "The role of histone deacetylases (HDACs) in human cancer", Mol Oncol 1:19-25</p>
<p>Sekhavat, A. et al. (2007), "Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate", Biochemistry and Cell Biology 85:751-758</p>
<p>Taunton, J. et al. (1996), "A mammalian histone deacetylase related to the Yeast transcriptional regulator Rpd3p", Science 272:408-411</p>
<p>Villar-Garea, A. and Esteller, M. (2004), "Histone deacetylase inhibitors: understanding a new wave of anticancer agents", Int J Cancer 112:171-178</p>
<p>Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831</p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Wagner F.F. et al. (2015), “Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhances”, Chem Sci 6:804</span></span></p>
<p>Weichert, W. (2009) "HDAC expression and clinical prognosis in human malignancies", Cancer Letters 280:168-176</p>
<p>Yanuar, A. et al. (2016), "In silico approach to finding new active compounds from histone deacetylase (HDAC) family", Curr Pharm Des 22:3488-3497</p>
<p>Zwick, V. et al. (2016), "Cell-based multi-substrate assay coupled to UHPLC-ESI-MS/MS for a quick identification of class-specific HDAC inhibitors", J Enzyme Inhib Med Chem 31:209-214</p>
2018-01-21T20:07:192022-07-14T16:18:05Neural crest cell migration, reducedReduced neural crest cell migrationCellular<p>Neural crest cell (NCC) migration is dependent on coordinated expressional alterations of a large number of genes, such as integrins, matrix metalloproteinases, and cytoskeletal components.</p>
<p>The differential regulation of a panel of such genes, has been investigated in an in vitro system, which found that histone deacetylases VPA, TSA, and SAHA exerted similar gene regulatory profiles which were quite distinct from those of other compounds shown to affect NCC migration in a scratch assay (Dreser et al., 2015). A similar experimental setup has applied a broader Affymetrix chip approach to identify biomarkers specific to the inhibition of NCC migration (Pallocca et al., 2016). In vivo evidence for the importance of specific HDACs to NCC migration has been provided by genetic knock down experiments in zebrafish embryos (DeLaurier et al., 2012).</p>
<p>It is likely that the NCC migratory inhibition exerted by HDAC inhibitors is, at least in part, due to the broad transcriptomic impact of HDAC action on histones. However, it cannot be excluded HDAC inhibition could, to some degree, be effects altered acetylation patterns on other proteins, e.g. tubulin acetylation has been shown to be affected by HDAC activity (Hubbert et al., 2002).</p>
<p>NCC migration can be assessed in vitro by scratch assays, and in vivo in developing zebrafish embryos by confocal microscopy with the sox10 fluorescent reporter fishline. Sox10 is a recognized marker of migratory NCCs (Britsch et al., 2001).</p>
<p>Britsch, S., Goerich, D.E., Riethmacher, D., Peirano, R.I., Rossner, M., Nave, K.A., et al. (2001), Genes Dev 15: 66–78.</p>
<p>DeLaurier, A., Nakamura, Y., Braasch, I., Khanna, V., Kato, H., Wakitani, S., et al. (2012), BMC Dev Biol 12: 16.</p>
<p>Dreser, N., Zimmer, B., Dietz, C., Sügis, E., Pallocca, G., Nyffeler, J., et al. (2015), Neurotoxicology 50: 56–70.</p>
<p>Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., et al. (2002), Nature 417: 455–458.</p>
<p>Pallocca, G., Grinberg, M., Henry, M., Frickey, T., Hengstler, J.G., Waldmann, T., et al. (2016), Arch Toxicol 90: 159–180.</p>
<p> </p>
2018-12-20T03:49:222018-12-20T04:10:02Collagen production, reducedReduced collagen productionTissue<p>Post-migratory cranial NCCs differentiate to give rise to chondrocytes which secrete collagen in order to form the cartilage structures which form the precursors of bony facial features (Bhatt et al., 2013).</p>
<p>Collagen expression is considered a marker for NCC differentiation into chondrocytes (Bhatt et al., 2013) and can be assessed in vivo by fluorescent microscopy using fluorescent collagen reporter zebrafish lines (Hammond and Schulte-Merker, 2009).</p>
<p>Bhatt, S., Diaz, R., Trainor, P. a, Wu, D.K., Kelley, M.W., Tam, P.L., et al. (2013), Cold Spring Harb Perspect Biol 5: 1–20.</p>
<p>Hammond, C.L., and Schulte-Merker, S. (2009), Development 136: 3991–4000.</p>
<p> </p>
2018-12-20T03:52:042018-12-20T04:15:17Facial cartilage structures are reduced in size and morphologically distortedSmaller and morphologically distorted facial cartilage structuresTissue<p>In order for cartilage structures to form, chondrocytes need to secrete large amounts of collagen. One outcome of the disturbances of NCC migration and differentiation is the distortion and reduced size of facial cartilage structures.</p>
<p>The appearance of facial cartilage structures is readily visible in ventral views of zebrafish embryos at 5 days post fertilization. Such structures as the ceratohyal, Meckel’s cartilage, and the palatoquadrate are visible using fluorescent collagen reporter lines. Measurements of the angle formed by the ceratohyal provide a quantitative readout.</p>
2018-12-20T03:53:052018-12-20T04:16:5103f28a1d-b159-41e3-8bcc-e1f6a0c7f1a032e46075-67c0-4c19-846a-ff2125e7d06d<p>Histone acetylation is regulated by the opposing actions of histone acetylases (HATs) and histone deacetylases (HDACs). Inhibition of HDACs will be lead to hyperacetylation of histones, relaxed chromatin structure and permissive transcription, ultimately resulting in broadly altered gene expression patterns. These alterations in gene expression patterns are likely to be, at least in part, the basis of observable reduction of migration of neural crest cells (NCCs).</p>
<p>The formation of neural crest cells (NCCs) takes place after neurulation in the developing embryo. Prior to migration, NCCs undergo epithelial to mesenchymal transition (EMT), characterized by extensively altered cellular morphology by the suppression of E-cadherin transcription (Bhatt et al., 2013). This transcriptional regulation, resulting in released cell adhesion is affected by transcription factors of the Snail family (Cano et al., 2000; Taneyhill et al., 2007; Bolos et al., 2016). The effect of HDAC inhibition on EMT has been studied most extensively in the context of cancer treatment, and numerous studies have been devoted to explore the effectiveness of chemical HDAC inhibitors as potential chemotherapeutics (Drummond et al., 2005). Several studies have found that HDAC inhibition attenuates EMT, though comparatively few focusing on EMT in pre-migratory NCCs. However chromatin immunoprecipitation experiments have demonstrated that a genetic loci of importance to EMT, a target of a Snail family transcription factor, in pre-migratory NCCs exhibits dramatic deacetylation at the time of EMT initiation (Strobl-Mazzulla and Bronner, 2012). This indicates that HDAC inhibition is likely to affect the process of EMT in NCCs as well. Furthermore, in vitro studies have shown attenuation of NCC migration in response to chemical HDAC inhibition (Dreser et al., 2015; Pallocca et al., 2016) and NCC migration has been shown to be affected in vivo by antisense mediated genetic knock down of a specific HDAC encoding gene (DeLaurier et al., 2012).</p>
<p>In vitro scratch assay data has shown reducing effects of HDAC inhibitors on the migration of NCCs. Different HDAC inhibitors have been shown to exert similar gene regulatory effects on NCCs in vitro (Dreser et al., 2015; Pallocca et al., 2016).<br />
Genetic manipulations have been applied in vivo to show that HDAC4 is important to cranial NCC migration in developing zebrafish (DeLaurier et al., 2012).</p>
<p>In an in vivo situation, it is uncertain whether observed reduction of NCC migration is caused by the effects of HDAC vs. HAT action on histones, or other proteins that exhibit altered acetylation patterns in response to HDAC inhibition, e.g. tubulin (Hubbert et al., 2002).<br />
Members of the Snail family of proteins have been reported to be dispensable in mammals (Murray and Gridley, 2006), indicating that conclusions regarding the importance of HDAC activity in relation to Snail regulation and EMT must be made with caution.</p>
<p>Bhatt, S., Diaz, R., Trainor, P. a, Wu, D.K., Kelley, M.W., Tam, P.L., et al. (2013), Cold Spring Harb Perspect Biol 5: 1–20.</p>
<p>Bolos, V., Peinado, H., Perez-Moreno, M.A., Fraga, M.F., Esteller, M., and Cano, A. (2016), J Cell Sci 129: 1283–1283</p>
<p>Cano, A., Pérez-Moreno, M.A., Rodrigo, I., Locascio, A., Blanco, M.J., Barrio, M.G. del, et al. (2000), Nat Cell Biol 2: 76–83</p>
<p>DeLaurier, A., Nakamura, Y., Braasch, I., Khanna, V., Kato, H., Wakitani, S., et al. (2012), BMC Dev Biol 12: 16</p>
<p>Dreser, N., Zimmer, B., Dietz, C., S??gis, E., Pallocca, G., Nyffeler, J., et al. (2015), Neurotoxicology 50: 56–70.</p>
<p>Drummond, D.C., Noble, C.O., Kirpotin, D.B., Guo, Z., Scott, G.K., and Benz, C.C. (2005), Annu Rev Pharmacol Toxicol 45: 495–528.</p>
<p>Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., et al. (2002), Nature 417: 455–458.</p>
<p>Murray, S.A., and Gridley, T. (2006), Proc Natl Acad Sci 103: 10300–10304.</p>
<p>Pallocca, G., Grinberg, M., Henry, M., Frickey, T., Hengstler, J.G., Waldmann, T., et al. (2016), Arch Toxicol 90: 159–180.</p>
<p>Strobl-Mazzulla, P.H., and Bronner, M.E. (2012), J Cell Biol 198: 999–1010.</p>
<p>Taneyhill, L.A., Coles, E.G., and Bronner-Fraser, M. (2007), Development 134: 1481–1490.</p>
2018-12-20T03:54:122018-12-20T04:22:3403f28a1d-b159-41e3-8bcc-e1f6a0c7f1a097446f96-fbc6-446f-896f-ff24da5a26b3<p>Post-migratory NCCs form the progenitor population from which collagen-secreting chondrocytes develop. In addition to the effects on NCC migration, specific HDACs may affect chondrogenesis by disturbing genetic inducers of chondrogenic differentiation, such as sox9, after NCC migration.</p>
<p>In zebrafish embryos, TSA mediated HDAC inhibition was found to drastically reduce cartilage formation when applied in a 24-hour window from 28 to 52 hours post fertilization (after NCC migration has occurred) (Ignatius et al., 2013). Furthermore a mutant, deficient in HDAC1, display no observable defects in NCC induction or migration (Ignatius et al., 2008), yet is highly attenuated in collagen secretion and development of craniofacial cartilage structures (Ignatius et al., 2013), indication a function for specific HDACs in chondrogenesis which is separate from NCC migration.</p>
<p>In ex vivo mouse limbs VPA mediated chemical HDAC inhibition was found to reduce sox9 and collagen type II (col2a1) expression, effects which correlated with reduced limb elongation (Paradis and Hales, 2013).<br />
In zebrafish, chemical HDAC inhibition can attenuate craniofacial cartilage formation after NCC migration is complete (Ignatius et al., 2013).</p>
<p>It is very likely that different HADCs serve different functions in the developing organism. Differences in spatiotemporal expression patterns or sensitivities of individual HDACs to specific chemical inhibitors will need extensive experimental work in order to be fully understood.</p>
<p>At present, it is well established that in developing zebrafish, that at least two HDACs (HDAC1 and HDAC4) are involved in chondrogenic development. But whether those are the only ones, and whether they are equally sensitive to the various classes of HDAC inhibitors remains to be elucidated.</p>
<p>Furthermore, it remains to be shown if the functions of genes identified in zebrafish, translates directly to those in humans.</p>
<p>Ignatius, M.S., Moose, H.E., El-Hodiri, H.M., and Henion, P.D. (2008), Dev Biol 313: 568–583.</p>
<p>Ignatius, M.S., Unal Eroglu, A., Malireddy, S., Gallagher, G., Nambiar, R.M., and Henion, P.D. (2013), PLoS One 8: 1–14.</p>
<p>Paradis, F.H., and Hales, B.F. (2013), Toxicol Sci 131: 234–241.</p>
2018-12-20T03:55:032018-12-20T04:33:4632e46075-67c0-4c19-846a-ff2125e7d06d97446f96-fbc6-446f-896f-ff24da5a26b3<p>Post-migratory NCCs form the progenitor population from which collagen-secreting chondrocytes develop. NCCs are progenitors of several different tissues and cell types, and their precise fate is regulated in a complex manner with influences from surrounding epithelial tissues (Bhatt et al., 2013). The migration and condensation of NCCs at their proper location is a prerequisite to their differentiation and collagen production.</p>
<p>The ultimate fate of the multipotent NCCs is only settled after migration and is controlled in a complex interplay of intrinsic and external signal cues. The overall migration patterns are well established and are conserved across vertebrates (Kulesa et al., 2004). Though the regulation is complex and there are gaps in our understanding, factors governing the overall NCC migration patterns and chondrogenic differentiation are fairly well understood (Bhatt et al., 2013; Hall, 2014). The defining trait of differentiated chondrocytes is the expression of collagen 2a, controlled by the transcription factor Sox9 (Ng et al., 1997; Mori-Akiyama et al., 2003). Sox9 is again controlled in a tissue-dependent manner through the actions of Hox genes and fibroblast growth factors (Trainor and Krumlauf, 2001) in order to define the structural features of the face.</p>
<p>In palatal development it has been shown that suppressed cranial NCC migration and subsequent reductions in NCC populations fail to recover at the post-migratory stage and that this suppressed NCC phenotype correlates with later cartilaginous defects (DeLaurier et al., 2012).</p>
<p>Critical numbers of NCC migrating to their destination has been shown to be an important factor in the development of other NCC derived tissues and cell systems (Barlow et al., 2008), but, to the best of our knowledge, this has not been shown directly in facial cartilage development.</p>
<p>Bhatt, S., Diaz, R., Trainor, P. a, Wu, D.K., Kelley, M.W., Tam, P.L., et al. (2013), Cold Spring Harb Perspect Biol 5: 1–20.</p>
<p>DeLaurier, A., Nakamura, Y., Braasch, I., Khanna, V., Kato, H., Wakitani, S., et al. (2012), BMC Dev Biol 12: 16.</p>
<p>Hall, B.K. (2014), Am J Med Genet Part A 164: 884–891.</p>
<p>Kulesa, P., Ellies, D.L., and Trainor, P.A. (2004), Dev Dyn 229: 14–29.</p>
<p>Mori-Akiyama, Y., Akiyama, H., Rowitch, D.H., and Crombrugghe, B. de (2003), Proc Natl Acad Sci 100: 9360–9365</p>
<p>Ng, L.-J., Wheatley, S., Muscat, G.E.., Conway-Campbell, J., Bowles, J., Wright, E., et al. (1997), Dev Biol 183: 108–121</p>
<p>Trainor, P.A., and Krumlauf, R. (2001), Curr Opin Cell Biol 13: 698–705.</p>
2018-12-20T03:54:282018-12-20T04:27:1697446f96-fbc6-446f-896f-ff24da5a26b30c7491b9-8343-4a89-916e-e027c9922044<p>The main component of cartilage is collagen, most importantly fibril forming type II collagen which forms the fibrillary scaffold to which other proteoglycans can crosslink (Van Der Rest and Mayne, 1988).</p>
<p>The expression and secretion of collagen from chondrocytes are vitally important to the morphological development and mechanical properties of cartilage structures.</p>
<p>The advent of the bony skeleton marks a significant evolutionary event and as such the evolution of the key components in its development has been studied extensively. The Sox9 regulated collagen secretion in cartilage development has been found to be a highly evolutionarily conserved feature (Zhang et al., 2006). It has been shown in several organisms that loss of function mutations in genes encoding collagens exhibit severe phenotypic manifestations in cartilages and cartilage-derived tissues (Vuorio and de Crombrugghe, 1990). In zebrafish, the reduced expression of otherwise functional type II collagen, due to a mutation in the Sox9 encoding gene, was characterized by severely retarded craniofacial cartilage formation (Yan et al., 2002).</p>
<p>A mouse mutant in type II collagen is severely deficient in cartilage formation (Garofalo et al., 1991).<br />
In zebrafish, antisense knock-down of col11a1, another fibrillar collagen, was found to cause severe attenuation of craniofacial cartilage development (Baas et al., 2009).</p>
<p>While it is quite well established that fibrillar collagens, such as collagen 2a and collagen 11a, are important to normal cartilage formation, and that null and dominant negative mutations will cause certain strong phenotypic manifestations within cartilage structures, it is less well established how reduced collagen expression will affect such structures. Whether measurable morphological manifestations, such as e.g. differing angles, diameters or lengths, of cartilage features, are in fact caused by attenuated cartilage expression or simply correlated with it, is unknown.</p>
<p>Baas, D., Malbouyres, M., Haftek-Terreau, Z., Guellec, D. Le, and Ruggiero, F. (2009), Matrix Biol 28: 490–502.</p>
<p>Garofalo, S., Vuorio, E., Metsaranta, M., Rosati, R., Toman, D., Vaughan, J., et al. (1991), Proc Natl Acad Sci U S A 88: 9648–9652.</p>
<p>Rest, M. Van Der, and Mayne, R. (1988), J Biol Chem 263: 1615–1618.</p>
<p>Vuorio, E., and Crombrugghe, B. de (1990), Annu Rev Biochem 59: 837–72</p>
<p>Yan, Y.L., Miller, C.T., Nissen, R.M., Singer, A., Liu, D., Kirn, A., et al. (2002), Development 129: 5065–5079</p>
<p>Zhang, G., Miyamoto, M.M., and Cohn, M.J. (2006), Proc Natl Acad Sci U S A 103: 3180–3185.</p>
2018-12-20T03:54:422018-12-20T04:30:32Histone deacetylase inhibition leads to impeded craniofacial developmentHDAC inhibition leads to impeded craniofacial development<p>Bjorn Koch, Annemarie Meijer, Herman Spaink, Thomas Braunbeck</p>
Under Development: Contributions and Comments Welcome<p style="text-align:justify">Histone deacetylases (HDACs) regulate gene expression through modulating chromatin structure and are known to impact many aspects of development in animals. Several compounds have been found to inhibit the action of HDACs leading to various adverse outcomes. This AOP aims to describe the sequence of events by which HDAC inhibition leads to impeded craniofacial development.<br />
The MIE is the inhibition, at early embryonic stages, of histone deacetylases. This leads to inhibition of cranial neural crest cell migration and inhibition of chondrocyte differentiation. The attenuation of chondrocyte differentiation reduces the production of collagen, a key structural component of cartilage, resulting in the reduced size and morphologically distorted facial cartilage features.<br />
This AOP concerns very specific developmental effects of an MIE which has very broad gene regulatory implications. This means that the progression through KEs and AO are mainly applicable at early developmental stages prior to neural crest migration and chondrocyte differentiation.<br />
The AOP is linked to case study 2, concerning the developmental and reproductive toxicity of valproic acid (VPA) and several structural homologs. One of the well-described developmental toxicity effects of fetal VPA exposure is craniofacial deformities.</p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">HDIs are classified according to chemical nature and mode of mechanism: the short-chain fatty acids (e.g., butyrate, valproate), hydroxamic acids (e.g., suberoylanilide hydroxamic acid or SAHA, Trichostatin A or TSA), cyclic tetrapeptides (e.g., FK-228), benzamides (e.g., N-acetyldinaline and MS-275) and epoxides (depeudecin, trapoxin A) [Richon et al., 2003; Ropero and Esteller, 2007; Villar-Garea et al., 2004]. There is a report showing that TSA and butyrate competitively inhibit HDAC activity [Sekhavat et al., 2007]. HDIs inhibit preferentially HDACs with some selectiveness [Hu et al., 2003]. TSA (Trichostatin A) inhibits class I and II of HDACs, while butyrate inhibits class I and IIa (HDACs 4, 5, 7, 9) of HDACs [Ooi et al., 2015; Park and Sohrabji, 2016; Wagner et al., 2015]. TSA inhibits HDAC1, 2, and 3 [Damaskos et al., 2016], whereas MS-27-275 has an inhibitory effect for HDAC1 and HDAC3 (IC<sub>50</sub> value of ~0.3 microM and ~8 microM, respectively), but no effect for HDAC8 (IC<sub>50</sub> value >100 microM) [Hu et al., 2003].</span></span></p>
adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot Specifiednon-adjacentNot SpecifiedNot SpecifiedNot SpecifiedNot SpecifiedNot SpecifiedNot SpecifiedNot SpecifiedNot Specified2018-12-20T03:45:232023-04-29T16:03:01