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histone acetylation

Adaobi Okonkwo, Joy Mitra, Gavin S Johnson, Li Li, Wan Mohaiza Dashwood, Muralidhar Hegde, Chen Yue, Roderick H Dashwood, Praveen Rajendran
SCOPE: DNA repair inhibitors have broad clinical applications in tumor types with DNA repair defects, including colorectal cancer. Structural analogs of the anticancer agent sulforaphane (SFN) were investigated as modifiers of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity, and for effects on DNA damage/repair pertinent to human colorectal cancer. METHODS AND RESULTS: In the polyposis in rat colon (Pirc) model, single oral administration of SFN and structurally-related long-chain isothiocyanates (ITCs) decreased HDAC3 expression and increased pH2AX levels markedly in adenomatous colon polyps, extending our prior observations on HDAC3 inhibition/turnover in cell-based assays...
June 20, 2018: Molecular Nutrition & Food Research
Jiah Lim, Yoojin Song, Jung-Hee Jang, Chul-Ho Jeong, Sooyeun Lee, Byoungduck Park, Young Ho Seo
Aspirin is one of the oldest drugs for the treatment of inflammation, fever, and pain. It is reported to covalently modify COX-2 enzyme by acetylating a serine amino acid residue. By virtue of aspirin's acetylating potential, we for the first time developed novel acetyl-donating HDAC inhibitors. In this study, we report the design, synthesis, in silico docking study, and biological evaluation of acetyl-donating HDAC inhibitors. The exposure of MDA-MB-231 cells with compound 4c significantly promotes the acetylation of α-tubulin and histone H3, which are substrates of HDAC6 and HDAC1, respectively...
June 20, 2018: Archives of Pharmacal Research
Cheng-Jun Hu, Hui Zhang, Aya Laux, Soni S Pullamsetti, Kurt R Stenmark
Chronic pulmonary hypertension (PH) is characterized by the accumulation of persistently activated cell types in the pulmonary vessel exhibiting aberrant expression of genes involved in apoptosis resistance, proliferation, inflammation, and ECM remodeling. Current therapies for PH, focusing on vasodilation, do not normalize these activated phenotypes. Furthermore, current approaches to define additional therapeutic targets have focused on determining the initiating signals and their downstream effectors that are important in PH onset and development...
June 19, 2018: Journal of Physiology
Surajit Ganguly, Subhendu Seth
A large volume of research now provides evidence correlating aberrant histone deacetylase (HDAC) activities and hypoacetylation of histones to disruptions in synaptic plasticity, neuronal survival/regeneration, memory formation and consolidation. Hence, maintaining the acetyl-histone homeostasis as a component of neuronal mechanisms by targeting HDACs has emerged as an exciting intervention strategy for several neuropsychiatric disorders. Though extensive preclinical animal studies have elevated the translational potential of HDAC inhibitors (HDACis) in psychiatric disorders, so far, the translational gain remains low...
June 19, 2018: Psychopharmacology
Damien Nicolas, Benjamin Zoller, David M Suter, Felix Naef
Many mammalian genes are transcribed during short bursts of variable frequencies and sizes that substantially contribute to cell-to-cell variability. However, which molecular mechanisms determine bursting properties remains unclear. To probe putative mechanisms, we combined temporal analysis of transcription along the circadian cycle with multiple genomic reporter integrations, using both short-lived luciferase live microscopy and single-molecule RNA-FISH. Using the Bmal1 circadian promoter as our model, we observed that rhythmic transcription resulted predominantly from variations in burst frequency, while the genomic position changed the burst size...
June 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
Gabrijela Dumbovic, Josep Biayna, Jordi Banús, Johanna Samuelsson, Anna Roth, Sven Diederichs, Sergio Alonso, Marcus Buschbeck, Manuel Perucho, Sonia-V Forcales
Primate-specific NBL2 macrosatellite is hypomethylated in several types of tumors, yet the consequences of this DNA hypomethylation remain unknown. We show that NBL2 conserved repeats are close to the centromeres of most acrocentric chromosomes. NBL2 associates with the perinucleolar region and undergoes severe demethylation in a subset of colorectal cancer (CRC). Upon DNA hypomethylation and histone acetylation, NBL2 repeats are transcribed in tumor cell lines and primary CRCs. NBL2 monomers exhibit promoter activity, and are contained within novel, non-polyA antisense lncRNAs, which we designated TNBL (Tumor-associated NBL2 transcript)...
April 18, 2018: Nucleic Acids Research
Li Liu, Xiaoyan Wu, Huihui Xu, Liming Yu, Xinjian Zhang, Luyang Li, Jianliang Jin, Tao Zhang, Yong Xu
A host of pathogenic factors induce acute kidney injury (AKI) leading to insufficiencies of renal function. In the present study we evaluated the role of myocardin-related transcription factor A (MRTF-A) in the pathogenesis of AKI. We report that systemic deletion of MRTF-A or inhibition of MRTF-A activity with CCG-1423 significantly attenuated AKI in mice induced by either ischemia-reperfusion or LPS injection. Of note, MRTF-A deficiency or suppression resulted in diminished renal ROS production in AKI models with down-regulation of NAPDH oxdiase 1 (NOX1) and NOX4 expression...
June 14, 2018: Biochimica et Biophysica Acta
Sanjay Singh, Sarfraj Ahmad Siddiqui, Sukanya Tripathy, Shiv Kumar, Sudipta Saha, Rajesh Ugale, Dinesh Raj Modi, Anand Prakash
In the last few decades, there has been exponential increase in studies aiming to trace the molecular mechanism of fear extinction with a hope to minimize the return of fear after exposure therapy required for operational treatment of anxiety disorders. The present study explored how the timing of extinction training after developing a specific fear, affects the consequent return of the extinguished fear and the role of histone acetylation in controlling the circuitry, thereof. It was found that rats undergone extinction training 10 min...
June 14, 2018: Brain Research Bulletin
Jung Sun Min, Jin Chul Kim, Ji Ae Kim, Inho Kang, Jeong Keun Ahn
SIRT2, a member of the class III histone deacetylase family, has been identified as a tumor suppressor, which is associated with various cellular processes including metabolism and proliferation. However, the effects of SIRT2 on cancer cell migration caused by cytoskeletal rearrangement remain uncertain. Here we show that SIRT2 inhibits cell motility by suppressing actin polymerization. SIRT2 regulates actin dynamics through HSP90 destabilization and subsequent repression of LIM kinase (LIMK) 1/cofilin pathway...
June 13, 2018: Biochimica et Biophysica Acta
Yasin Pourfarjam, Jessica Ventura, Igor Kurinov, Ahra Cho, Joel Moss, In-Kwon Kim
ADP-ribosyl-acceptor hydrolase 3 (ARH3) plays important roles in regulation of poly(ADP-ribosy)lation, a reversible post-translational modification, and in maintenance of genomic integrity. ARH3 degrades poly(ADP-ribose) to protect cells from poly(ADP-ribose)-dependent cell death, reverses serine-mono(ADP-ribosy)lation, and hydrolyzes O -acetyl-ADP-ribose, a product of Sirtuin-catalyzed histone deacetylation. ARH3 preferentially hydrolyzes O-linkages attached to the anomeric C1″ of ADP-ribose; however, how ARH3 specifically recognizes and cleaves structurally diverse substrates remains unknown...
June 15, 2018: Journal of Biological Chemistry
Michael Weykamp, Vahagn C Nikolian, Isabel S Dennahy, Gerald A Higgins, Patrick E Georgoff, Henriette Remmer, Mohamed H Ghandour, Hasan B Alam
BACKGROUND: Histone deacetylase inhibitors such as valproic acid (VPA) improve survival in lethal models of hemorrhagic shock and polytrauma. Although VPA is known to modulate transcription, its ability to reduce mortality within minutes of administration suggests involvement of a rapid, posttranslational mechanism. We hypothesized that VPA treatment would cause proteomic changes within minutes of treatment including quantitative and/or posttranslational differences in structural and/or effector proteins...
August 2018: Journal of Surgical Research
Emmanuelle Gouot, Wajid Bhat, Anne Rufiange, Eric Fournier, Eric Paquet, Amine Nourani
CK2 is an essential protein kinase implicated in various cellular processes. In this study, we address a potential role of this kinase in chromatin modulations associated with transcription. We found that CK2 depletion from yeast cells leads to replication-independent increase of histone H3K56 acetylation and global activation of H3 turnover in coding regions. This suggests a positive role of CK2 in maintenance/recycling of the histone H3/H4 tetramers during transcription. Interestingly, strand-specific RNA-seq analyses show that CK2 inhibits global cryptic promoters driving both sense and antisense transcription...
June 14, 2018: Nucleic Acids Research
Min Liu, Biao Chen, Linguo Pei, Qi Zhang, Yunfei Zou, Hao Xiao, Jin Zhou, Liaobin Chen, Hui Wang
Prenatal dexamethasone exposure (PDE) could induce testicular developmental toxicity in adults. The present study aims to confirm its intrauterine origination, and to explore its potential intrauterine programming mechanism. The pregnant rats were respectively injected subcutaneously with 0.2 and 0.8 mg/kg⋅d dexamethasone during gestational days (GD) 9 to 20. The testes and serum of offspring rats were collected on GD20 and postnatal week (PW) 12. In vivo, PDE significantly induced the abnormal testicular morphology in offspring from GD20 to PW12...
June 11, 2018: Toxicology
Wanlin Jiang, Devendra K Agrawal, Chandra S Boosani
Histone modifications are the key epigenetic mechanisms that have been identified to regulate gene expression in many human diseases. However, in the early developmental stages, such as in utero and the postnatal stages, histone modifications are essential for gene regulation and cell growth. Atherosclerosis represents a classical example of the involvement of different cell types, and their cumulative effects in the development of atheroma and the progression of the disease. Post translational modifications on proteins either induces their functional activity or renders them inactive...
June 6, 2018: Molecular Medicine Reports
Chih-Chao Hsu, Dan Zhao, Jiejun Shi, Danni Peng, Haipeng Guan, Yuanyuan Li, Yaling Huang, Hong Wen, Wei Li, Haitao Li, Xiaobing Shi
The histone variant H2A.Z is essential for maintaining embryonic stem cell (ESC) identity in part by keeping developmental genes in a poised bivalent state. However, how H2A.Z is deposited into the bivalent domains remains unknown. In mammals, two chromatin remodeling complexes, Tip60/p400 and SRCAP, exchange the canonical histone H2A for H2A.Z in the chromatin. Here we show that Glioma Amplified Sequence 41 (Gas41), a shared subunit of the two H2A.Z-depositing complexes, functions as a reader of histone lysine acetylation and recruits Tip60/p400 and SRCAP to deposit H2A...
2018: Cell Discovery
María G García, Antonella Carella, Rocío G Urdinguio, Gustavo F Bayón, Virginia Lopez, Juan Ramón Tejedor, Marta I Sierra, Estela García-Toraño, Pablo Santamarina, Raúl F Perez, Cristina Mangas, Aurora Astudillo, M Daniela Corte-Torres, Inés Sáenz-de-Santa-María, María-Dolores Chiara, Agustín F Fernández, Mario F Fraga
Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma...
May 25, 2018: Oncotarget
Hongyue Zhang, Ying Liu, Lixin Yan, Min Zhang, Xiufeng Yu, Wei Du, Siqi Wang, Qiaozhi Li, He Chen, Yafeng Zhang, Hanliang Sun, Zhidong Tang, Daling Zhu
Many long noncoding RNAs (lncRNAs) have been identified as powerful regulators of lung adenocarcinoma (LAD). However, the role of HOXA-AS3, a novel lncRNA, in LAD is largely unknown. In this study, we showed that HOXA-AS3 was significantly upregulated in LAD tissues and A549 cells. After knockdown of HOXA-AS3, cell proliferation, migration, and invasion were inhibited. Xenografts derived from A549 cells transfected with shRNA/HOXA-AS3 had significantly lower tumor weights and smaller tumor volumes. We also demonstrated that HOXA-AS3 increased HOXA6 mRNA stability by forming an RNA duplex...
June 13, 2018: Cell Death & Disease
Bing Yan, Songbo Xie, Yang Liu, Wenxuan Liu, Dengwen Li, Min Liu, Hongbo R Luo, Jun Zhou
Mice with histone deacetylase 6 (HDAC6) deficiency grow and develop normally but exhibit impaired immune response. The molecular mechanisms for this phenotype remain largely elusive. Methods: A mouse acute peritonitis model was used to study the infiltration of neutrophils and monocyte-derived macrophages. In vitro cell motility assays were performed to analyze monocyte/macrophage recruitment. Fluorescence microscopy and flow cytometry were performed to examine the phagocytic ability of macrophages. Immunofluorescence microscopy was used to investigate protein localization, protrusion formation, and microtubule acetylation...
2018: Theranostics
A A Serandour, H Mohammed, A Miremadi, K W Mulder, J S Carroll
The chromatin state is finely tuned to regulate function and specificity for transcription factors such as oestrogen receptor alpha (ER), which contributes to cell growth in breast cancer. ER transcriptional potential is mediated, in large part, by the specific associated proteins and co-factors that interact with it. Despite the identification and characterisation of several ER coregulators, a complete and systematic view of ER-regulating chromatin modifiers is lacking. By exploiting a focused siRNA screen that investigated the requirement for a library of 330 chromatin regulators in ER-mediated cell growth, we find that the NuRD and coREST histone deacetylation complexes are critical for breast cancer cell proliferation...
June 12, 2018: Oncogene
Shigeki Nishitani, Atsunori Fukuhara, Jihoon Shin, Yosuke Okuno, Michio Otsuki, Iichiro Shimomura
Sodium/glucose cotransporter 2 (SGLT2) inhibitor improves systemic glucose metabolism. To clarify the effect of dapagliflozin, we performed gene expression microarray and metabolomic analyses of murine adipose tissue. Three groups of mice were used; non-diabetic control KK mice (KK), diabetic KKAy mice (KKAy), and KKAy mice treated with dapagliflozin (KKAy + Dapa). Plasma glucose levels were significantly reduced in KKAy + Dapa compared with KKAy. Food consumption was larger in KKAy + Dapa than KKAy, and there were no significant differences in body and adipose tissue weight among the groups...
June 11, 2018: Scientific Reports
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