Key Spec Table
|Species Reactivity||Key Applications||Host||Format||Antibody Type|
|T, H||ICC, IP, WB, ChIP||Rb||Purified||Polyclonal Antibody|
|Safety Information according to GHS|
|Material Size||200 µg|
|Anti-acetyl-Histone H4 - 2387828||2387828|
|Anti-acetyl-Histone H4 - 2424765||2424765|
|Anti-acetyl-Histone H4 - 15793||15793|
|Anti-acetyl-Histone H4 - 16728||16728|
|Anti-acetyl-Histone H4 - 17942||17942|
|Anti-acetyl-Histone H4 - 19602||19602|
|Anti-acetyl-Histone H4 - 2019720||2019720|
|Anti-acetyl-Histone H4 - 2302181||2302181|
|Anti-acetyl-Histone H4 - 23224||23224|
|Reference overview||Application||Species||Pub Med ID|
|Berberine reverses abnormal expression of L-type pyruvate kinase by DNA demethylation and histone acetylation in the livers of the non-alcoholic fatty disease rat.|
Zhang, Y; Chang, X; Song, X; Chen, C; Chen, H; Lu, Z; Gao, X; Lu, D
Int J Clin Exp Med 8 7535-43 2015
Berberine (BBR) can potentially be used as a drug against non-alcoholic fatty liver disease (NAFLD) and diabetes. Our previous study found that BBR could change the pattern of DNA methylation. But the mechanisms underlying berberine are still far from completely understood. In this study, the function of L-PK in cell metabolism was explored, and high-fat-diet induced SD rats NAFLD models were created. The NAFLD rats were randomly grouped to be oral administration with BBR at a dosage of 200 mg/kg daily. Then DNA methylation and histone acetylation around the L-type Pyruvate Kinase (L-PK) gene were examined. In the results, we found that L-PK had a positive effect on cell proliferation, glucose utilization and triglyceride metabolism. However, the expression of L-PK was reduced in the livers of NAFLD rats, in accord with the decrease of DNA hypermethylation and histone deacetylation in the regulatory regions of L-PK. Notably, BBR treatment can restore the expression of L-PK by the demethylation of L-PK promoter and the increase in acetylation levels of histone H3 and H4 around L-PK, which indicated that BBR may be a potential drug for epigenetic-included diseases.
|Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area.|
Koo, JW; Mazei-Robison, MS; LaPlant, Q; Egervari, G; Braunscheidel, KM; Adank, DN; Ferguson, D; Feng, J; Sun, H; Scobie, KN; Damez-Werno, DM; Ribeiro, E; Peña, CJ; Walker, D; Bagot, RC; Cahill, ME; Anderson, SA; Labonté, B; Hodes, GE; Browne, H; Chadwick, B; Robison, AJ; Vialou, VF; Dias, C; Lorsch, Z; Mouzon, E; Lobo, MK; Dietz, DM; Russo, SJ; Neve, RL; Hurd, YL; Nestler, EJ
Nature neuroscience 18 415-22 2015
Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.
|Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor.|
Kim, GH; Oh, GS; Yoon, J; Lee, GG; Lee, KU; Kim, SW
The Journal of clinical investigation 125 183-93 2015
Inflammation in response to excess low-density lipoproteins in the blood is an important driver of atherosclerosis development. Due to its ability to enhance ATP-binding cassette A1-dependent (ABCA1-dependent) reverse cholesterol transport (RCT), liver X receptor (LXR) is an attractive target for the treatment of atherosclerosis. However, LXR also upregulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), leading to increased hepatic triglyceride synthesis, an independent risk factor for atherosclerosis. Here, we developed a strategy to separate the favorable and unfavorable effects of LXR by exploiting the specificity of the coactivator thyroid hormone receptor-associated protein 80 (TRAP80). Using human hepatic cell lines, we determined that TRAP80 selectively promotes the transcription of SREBP-1c but not ABCA1. Adenovirus-mediated expression of shTRAP80 inhibited LXR-dependent SREBP-1c expression and RNA polymerase II recruitment to the LXR responsive element (LXRE) of SREBP-1c, but not to the LXRE of ABCA1. In murine models, liver-specific knockdown of TRAP80 ameliorated liver steatosis and hypertriglyceridemia induced by LXR activation and maintained RCT stimulation by the LXR ligand. Together, these data indicate that TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. Moreover, targeting the interaction between TRAP80 and LXR should facilitate the development of potential LXR agonists that effectively prevent atherosclerosis.
|Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer.|
Wang, G; Niu, X; Zhang, W; Caldwell, JT; Edwards, H; Chen, W; Taub, JW; Zhao, L; Ge, Y
Cancer letters 356 656-68 2015
Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan-histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with MK-1775 to enhance cell death in preclinical pancreatic cancer models. We demonstrate that MK-1775 treatment results in increased H2AX phosphorylation, indicating increased DNA double-strand breaks, and activation of CHK1, which are both dependent on CDK activity. Combination of MK-1775 and panobinostat resulted in synergistic antitumor activity in six pancreatic cancer cell lines. Finally, our in vivo study using a pancreatic xenograft model reveals promising cooperative antitumor activity between MK-1775 and panobinostat. Our study provides compelling evidence that the combination of MK-1775 and panobinostat has antitumor activity in preclinical models of pancreatic cancer and supports the clinical development of panobinostat in combination with MK-1775 for the treatment of this deadly disease.
|ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat.|
Meidhof, S; Brabletz, S; Lehmann, W; Preca, BT; Mock, K; Ruh, M; Schüler, J; Berthold, M; Weber, A; Burk, U; Lübbert, M; Puhr, M; Culig, Z; Wellner, U; Keck, T; Bronsert, P; Küsters, S; Hopt, UT; Stemmler, MP; Brabletz, T
EMBO molecular medicine 7 831-47 2015
Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial-mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR-203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR-203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism-based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer.
|Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.|
Lu, H; Xue, Y; Xue, Y; Yu, GK; Arias, C; Lin, J; Fong, S; Faure, M; Weisburd, B; Ji, X; Mercier, A; Sutton, J; Luo, K; Gao, Z; Zhou, Q
eLife 4 e06535 2015
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.
|5-Hydroxymethylcytosine Plays a Critical Role in Glioblastomagenesis by Recruiting the CHTOP-Methylosome Complex.|
Takai, H; Masuda, K; Sato, T; Sakaguchi, Y; Suzuki, T; Suzuki, T; Koyama-Nasu, R; Nasu-Nishimura, Y; Katou, Y; Ogawa, H; Morishita, Y; Kozuka-Hata, H; Oyama, M; Todo, T; Ino, Y; Mukasa, A; Saito, N; Toyoshima, C; Shirahige, K; Akiyama, T
Cell reports 9 48-60 2014
The development of cancer is driven not only by genetic mutations but also by epigenetic alterations. Here, we show that TET1-mediated production of 5-hydroxymethylcytosine (5hmC) is required for the tumorigenicity of glioblastoma cells. Furthermore, we demonstrate that chromatin target of PRMT1 (CHTOP) binds to 5hmC. We found that CHTOP is associated with an arginine methyltransferase complex, termed the methylosome, and that this promotes the PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) in genes involved in glioblastomagenesis, including EGFR, AKT3, CDK6, CCND2, and BRAF. Moreover, we found that CHTOP and PRMT1 are essential for the expression of these genes and that CHTOP is required for the tumorigenicity of glioblastoma cells. These results suggest that 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancer-related genes.
|NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks.|
Vidi, PA; Liu, J; Salles, D; Jayaraman, S; Dorfman, G; Gray, M; Abad, P; Moghe, PV; Irudayaraj, JM; Wiesmüller, L; Lelièvre, SA
Nucleic acids research 42 6365-79 2014
Chromatin remodeling factors play an active role in the DNA damage response by shaping chromatin to facilitate the repair process. The spatiotemporal regulation of these factors is key to their function, yet poorly understood. We report that the structural nuclear protein NuMA accumulates at sites of DNA damage in a poly[ADP-ribose]ylation-dependent manner and functionally interacts with the ISWI ATPase SNF2h/SMARCA5, a chromatin remodeler that facilitates DNA repair. NuMA coimmunoprecipitates with SNF2h, regulates its diffusion in the nucleoplasm and controls its accumulation at DNA breaks. Consistent with NuMA enabling SNF2h function, cells with silenced NuMA exhibit reduced chromatin decompaction after DNA cleavage, lesser focal recruitment of homologous recombination repair factors, impaired DNA double-strand break repair in chromosomal (but not in episomal) contexts and increased sensitivity to DNA cross-linking agents. These findings reveal a structural basis for the orchestration of chromatin remodeling whereby a scaffold protein promotes genome maintenance by directing a remodeler to DNA breaks.
|H3K79 methylation: a new conserved mark that accompanies H4 hyperacetylation prior to histone-to-protamine transition in Drosophila and rat.|
Dottermusch-Heidel, C; Gärtner, SM; Tegeder, I; Rathke, C; Barckmann, B; Bartkuhn, M; Bhushan, S; Steger, K; Meinhardt, A; Renkawitz-Pohl, R
Biology open 3 444-52 2014
During spermiogenesis, haploid spermatids undergo extensive chromatin remodeling events in which histones are successively replaced by more basic protamines to generate highly compacted chromatin. Here we show for the first time that H3K79 methylation is a conserved feature preceding the histone-to-protamine transition in Drosophila melanogaster and rat. During Drosophila spermatogenesis, the Dot1-like methyltransferase Grappa (Gpp) is primarily expressed in canoe stage nuclei. The corresponding H3K79 methylation is a histone modification that precedes the histone-to-protamine transition and correlates with histone H4 hyperacetylation. When acetylation was inhibited in cultured Drosophila testes, nuclei were smaller and chromatin was compact, Gpp was little synthesized, H3K79 methylation was strongly reduced, and protamines were not synthesized. The Gpp isoform Gpp-D has a unique C-terminus, and Gpp is essential for full fertility. In rat, H3K79 methylation also correlates with H4 hyperacetylation but not with active RNA polymerase II, which might point towards a conserved function in chromatin remodeling during the histone-to-protamine transition in both Drosophila and rat.
|MRTF-A steers an epigenetic complex to activate endothelin-induced pro-inflammatory transcription in vascular smooth muscle cells.|
Yang, Y; Cheng, X; Tian, W; Zhou, B; Wu, X; Xu, H; Fang, F; Fang, M; Xu, Y
Nucleic acids research 42 10460-72 2014
Endothelin (ET-1) was initially identified as a potent vasoconstrictor contributing to the maintenance of vascular rhythm. Later studies have implicated ET-1, when aberrantly up-regulated within the vasculature, in a range of human pathologies associated with disruption of vascular homeostasis. ET-1 has been shown to invoke strong pro-inflammatory response in vascular smooth muscle cells (VSMCs); the underlying mechanism, however, remains elusive. Here, we report that the transcriptional modulator MRTF-A mediates the activation of pro-inflammatory mediators by ET-1 in VSMCs. ET-1 increased nuclear enrichment and activity of MRTF-A in cultured VSMCs. MRTF-A silencing attenuated ET-1 induced synthesis and release of pro-inflammatory mediators including IL-6, MCP-1 and IL-1 likely as a result of diminished NF-κB activity. In addition, MRTF-A was indispensible for the accumulation of active histone modifications on the gene promoters. Of intrigue, MRTF-A interacted with and recruited ASH2, a component of the mammalian histone methyltransferase complex, to transactivate pro-inflammatory genes in response to ET-1 treatment. The chromatin remodeling proteins BRG1 and BRM were also required for ET-1-dependent induction of pro-inflammatory mediators by communicating with ASH2, a process dependent on MRTF-A. In conclusion, our data have identified a novel epigenetic complex responsible for vascular inflammation inflicted by ET-1.