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https://www.readbyqxmd.com/read/28527406/the-relevance-of-ki-calculation-for-bi-substrate-enzymes-illustrated-by-kinetic-evaluation-of-a-novel-lysine-k-acetyltransferase-8-inhibitor
#1
Hannah Wapenaar, Thea van den Bosch, Niek G J Leus, Petra E van der Wouden, Nikolaos Eleftheriadis, Jos Hermans, Gebremedhin Solomon Hailu, Dante Rotili, Antonello Mai, Alexander Dömling, Rainer Bischoff, Hidde J Haisma, Frank J Dekker
Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28512251/inhibition-of-the-cell-death-pathway-in-nonalcoholic-steatohepatitis-nash-related-hepatocarcinogenesis-is-associated-with-histone-h4-lysine-16-deacetylation
#2
Aline de Conti, Kostiantyn Dreval, Volodymyr Tryndyak, Orish E Orisakwe, Sharon A Ross, Frederick A Beland, Igor P Pogribny
Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers, and its incidence is steadily increasing worldwide. Recent epidemiologic findings have suggested that the increased incidence of HCC is associated with obesity, type II diabetes mellitus, and nonalcoholic steatohepatitis (NASH); however, the mechanisms and the molecular pathogenesis of NASH-related HCC are not fully understood. To elucidate the underlying mechanisms of the development of NASH-related HCC, we investigated the hepatic transcriptomic and histone modification profiles in Stelic Animal Model mice, the first animal model of NASH-related HCC to resemble the disease pathogenesis in humans...
May 16, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28510597/ubiquitylation-of-the-acetyltransferase-mof-in-drosophila-melanogaster
#3
Sarah Schunter, Raffaella Villa, Victoria Flynn, Jan B Heidelberger, Anne-Kathrin Classen, Petra Beli, Peter B Becker
The nuclear acetyltransferase MOF (KAT8 in mammals) is a subunit of at least two multi-component complexes involved in transcription regulation. In the context of complexes of the 'Non-Specific-Lethal' (NSL) type it controls transcription initiation of many nuclear housekeeping genes and of mitochondrial genes. While this function is conserved in metazoans, MOF has an additional, specific function in Drosophila in the context of dosage compensation. As a subunit of the male-specific-lethal dosage compensation complex (MSL-DCC) it contributes to the doubling of transcription output from the single male X chromosome by acetylating histone H4...
2017: PloS One
https://www.readbyqxmd.com/read/28506985/histone-acetyltransferase-kat8-is-essential-for-mouse-oocyte-development-by-regulating-reactive-oxygen-species-levels
#4
Shi Yin, Xiaohua Jiang, Hanwei Jiang, Qian Gao, Fang Wang, Suixing Fan, Teka Khan, Nazish Jabeen, Manan Khan, Asim Ali, Peng Xu, Tej K Pandita, Heng-Yu Fan, Yuanwei Zhang, Qinghua Shi
Proper oocyte development is crucial for female fertility and requires timely and accurate control of gene expression. K (lysine) acetyltransferase 8 (KAT8), an important component of the X chromosome dosage compensation system in Drosophila, regulates gene activity by acetylating histone H4 preferentially at lysine 16. To explore the function of KAT8 during mouse oocyte development, we crossed Kat8(flox/flox) mice with Gdf9-Cre mice to specifically delete Kat8 in oocytes. Oocyte Kat8 deletion resulted in female infertility, with follicle development failure in the secondary and preantral follicle stages...
June 15, 2017: Development
https://www.readbyqxmd.com/read/28323055/a-6-alkylsalicylate-histone-acetyltransferase-inhibitor-inhibits-histone-acetylation-and-pro-inflammatory-gene-expression-in-murine-precision-cut-lung-slices
#5
Thea van den Bosch, Niek G J Leus, Hannah Wapenaar, Alexander Boichenko, Jos Hermans, Rainer Bischoff, Hidde J Haisma, Frank J Dekker
Lysine acetylations are post-translational modifications of cellular proteins, that are crucial in the regulation of many cellular processes. Lysine acetylations on histone proteins are part of the epigenetic code regulating gene expression and are installed by histone acetyltransferases. Observations that inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease, are characterized by increased histone acetyltransferase activity indicate that development of small molecule inhibitors for these enzymes might be a valuable approach towards new therapies for these diseases...
June 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28004786/gps-pail-prediction-of-lysine-acetyltransferase-specific-modification-sites-from-protein-sequences
#6
Wankun Deng, Chenwei Wang, Ying Zhang, Yang Xu, Shuang Zhang, Zexian Liu, Yu Xue
Protein acetylation catalyzed by specific histone acetyltransferases (HATs) is an essential post-translational modification (PTM) and involved in the regulation a broad spectrum of biological processes in eukaryotes. Although several ten thousands of acetylation sites have been experimentally identified, the upstream HATs for most of the sites are unclear. Thus, the identification of HAT-specific acetylation sites is fundamental for understanding the regulatory mechanisms of protein acetylation. In this work, we first collected 702 known HAT-specific acetylation sites of 205 proteins from the literature and public data resources, and a motif-based analysis demonstrated that different types of HATs exhibit similar but considerably distinct sequence preferences for substrate recognition...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27842509/unravelling-the-genomic-architecture-of-bull-fertility-in-holstein-cattle
#7
Yi Han, Francisco Peñagaricano
BACKGROUND: Fertility is considered an important economic trait in dairy cattle. Most studies have investigated cow fertility while bull fertility has received much less consideration. The main objective of this study was to perform a comprehensive genomic analysis in order to unravel the genomic architecture underlying sire fertility in Holstein dairy cattle. The analysis included the application of alternative genome-wide association mapping approaches and the subsequent use of diverse gene set enrichment tools...
November 14, 2016: BMC Genetics
https://www.readbyqxmd.com/read/27827827/histone-acetyltransferase-activity-of-mof-is-required-for-adult-but-not-early-fetal-hematopoiesis-in-mice
#8
Daria G Valerio, Haiming Xu, Meghan E Eisold, Carolien M Woolthuis, Tej K Pandita, Scott A Armstrong
K(lysine) acetyltransferase 8 (KAT8, also known as MOF) mediates the acetylation of histone H4 at lysine 16 (H4K16ac) and is crucial for murine embryogenesis. Lysine acetyltransferases have been shown to regulate various stages of normal hematopoiesis. However, the function of MOF in hematopoietic stem cell (HSC) development has not yet been elucidated. We set out to study the role of MOF in general hematopoiesis by using a Vav1-cre-induced conditional murine Mof knockout system and found that MOF is critical for hematopoietic cell maintenance and HSC engraftment capacity in adult hematopoiesis...
January 5, 2017: Blood
https://www.readbyqxmd.com/read/27758890/destabilization-of-fatty-acid-synthase-by-acetylation-inhibits-de-novo-lipogenesis-and-tumor-cell-growth
#9
Huai-Peng Lin, Zhou-Li Cheng, Ruo-Yu He, Lei Song, Meng-Xin Tian, Li-Sha Zhou, Beezly S Groh, Wei-Ren Liu, Min-Biao Ji, Chen Ding, Ying-Hong Shi, Kun-Liang Guan, Dan Ye, Yue Xiong
Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27709438/3d-structure-prediction-of-histone-acetyltransferase-proteins-of-the-myst-family-and-their-interactome-in-arabidopsis-thaliana
#10
A V Raevsky, M Sharifi, D A Samofalova, P A Karpov, Y B Blume
Histone lysine acetylation is a reversible post-translational modification that does not involve changes in DNA sequences. Enzymes play an important role in developmental processes and their deregulation has been linked to the progression of diverse disorders. The HAT enzyme family fulfills an important role in various developmental processes mediated by the state of chromatin, and have been attributed to its deregulation. To understand acetylation mechanisms and their role in cell signaling, transcriptional regulation, and apoptosis, it is crucial to identify and analyze acetylation sites...
November 2016: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/27285315/hexavalent-chromium-cr-vi-down-regulates-acetylation-of-histone-h4-at-lysine-16-through-induction-of-stressor-protein-nupr1
#11
Danqi Chen, Thomas Kluz, Lei Fang, Xiaoru Zhang, Hong Sun, Chunyuan Jin, Max Costa
The environmental and occupational carcinogen Hexavalent Chromium (Cr(VI)) has been shown to cause lung cancer in humans when inhaled. In spite of a considerable research effort, the mechanisms of Cr(VI)-induced carcinogenesis remain largely unknown. Nupr1 (nuclear protein 1) is a small, highly basic, and unfolded protein with molecular weight of 8,800 daltons and is induced by a variety of stressors. Studies in animal models have suggested that Nupr1 is a key factor in the development of lung and pancreatic cancers, with little known about the underlying molecular mechanisms...
2016: PloS One
https://www.readbyqxmd.com/read/27268279/kat8-regulates-androgen-signaling-in-prostate-cancer-cells
#12
Ji-Young Kim, Jindan Yu, Sarki A Abdulkadir, Debabrata Chakravarti
Androgen receptor (AR) plays pivotal roles in prostate cancer. Upon androgen stimulation, AR recruits the Protein kinase N1 (PKN1), which phosphorylates histone H3 at threonine 11, with subsequent recruitment of tryptophan, aspartic acid (WD) repeat-containing protein 5 (WDR5) and the su(var)3-9, enhancer of zeste, trithorax/mixed-lineage leukemia (SET1/MLL) histone methyltransferase complex to promote AR target gene activation and prostate cancer cell growth. However, the underlying mechanisms of target gene activation and cell growth subsequent to WDR5 recruitment are not well understood...
August 2016: Molecular Endocrinology
https://www.readbyqxmd.com/read/27050463/identification-of-modulators-of-autophagic-flux-in-an-image-based-high-content-sirna-screen
#13
Christopher M Hale, Qingwen Cheng, Danny Ortuno, Ming Huang, Dana Nojima, Paul D Kassner, Songli Wang, Michael M Ollmann, Holly J Carlisle
Autophagy is the primary process for recycling cellular constituents through lysosomal degradation. In addition to nonselective autophagic engulfment of cytoplasm, autophagosomes can recognize specific cargo by interacting with ubiquitin-binding autophagy receptors such as SQSTM1/p62 (sequestosome 1). This selective form of autophagy is important for degrading aggregation-prone proteins prominent in many neurodegenerative diseases. We carried out a high content image-based siRNA screen (4 to 8 siRNA per gene) for modulators of autophagic flux by monitoring fluorescence of GFP-SQSTM1 as well as colocalization of GFP-SQSTM1 with LAMP2 (lysosomal-associated membrane protein 2)-positive lysosomal vesicles...
2016: Autophagy
https://www.readbyqxmd.com/read/26767057/histone-acetylation-and-histone-acetyltransferases-show-significant-alterations-in-human-abdominal-aortic-aneurysm
#14
Yanshuo Han, Fadwa Tanios, Christian Reeps, Jian Zhang, Kristina Schwamborn, Hans-Henning Eckstein, Alma Zernecke, Jaroslav Pelisek
BACKGROUND: Epigenetic modifications may play a relevant role in the pathogenesis of human abdominal aortic aneurysm (AAA). The aim of the study was therefore to investigate histone acetylation and expression of corresponding lysine [K] histone acetyltransferases (KATs) in AAA. RESULTS: A comparative study of AAA tissue samples (n = 37, open surgical intervention) and healthy aortae (n = 12, trauma surgery) was performed using quantitative PCR, immunohistochemistry (IHC), and Western blot...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/26651296/in-vitro-maturation-affects-chromosome-segregation-spindle-morphology-and-acetylation-of-lysine-16-on-histone-h4-in-horse-oocytes
#15
Federica Franciosi, Ghylene Goudet, Irene Tessaro, Pascal Papillier, Rozenn Dalbies-Tran, Fabrice Reigner, Stefan Deleuze, Cecile Douet, Ileana Miclea, Valentina Lodde, Alberto M Luciano
Implantation failure and genetic developmental disabilities in mammals are caused by errors in chromosome segregation originating mainly in the oocyte during meiosis I. Some conditions, like maternal ageing or in vitro maturation (IVM), increase the incidence of oocyte aneuploidy. Here oocytes from adult mares were used to investigate oocyte maturation in a monovulatory species. Experiments were conducted to compare: (1) the incidence of aneuploidy, (2) the morphology of the spindle, (3) the acetylation of lysine 16 on histone H4 (H4K16) and (4) the relative amount of histone acetyltransferase 1 (HAT1), K(lysine) acetyltransferase 8 (KAT8, also known as MYST1), histone deacetylase 1 (HDAC1) and NAD-dependent protein deacetylase sirtuin 1 (SIRT1) mRNA in metaphase II stage oocytes that were in vitro matured or collected from peri-ovulatory follicles...
December 14, 2015: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/26640654/identification-of-acetyltransferase-genes-hat1-and-kat8-regulating-hbv-replication-by-rnai-screening
#16
Hui Wang, KeHui Liu, Bernard A M Fang, HaiQing Wu, FengDi Li, XiaoGang Xiang, WeiLiang Tang, GangDe Zhao, LanYi Lin, Shisan Bao, Qing Xie
BACKGROUND: The initiation of hepatitis B virus (HBV) replication involves the formation of covalently closed circular DNA (cccDNA) and its transcription into pregenomic RNA (pgRNA) in hepatocyte nuclei. The regulatory mechanism of HBV replication by acetyltransferase is thus far not well understood, but human acetyltransferase has been reported as being involved in the regulation of HBV replication. RESULTS: Depletion of KAT8 or HAT1 via RNA interference (RNAi) markedly down-regulated HBV-DNA and pgRNA levels in HepG2...
2015: Cell & Bioscience
https://www.readbyqxmd.com/read/26505788/enzyme-kinetics-and-inhibition-of-histone-acetyltransferase-kat8
#17
Hannah Wapenaar, Petra E van der Wouden, Matthew R Groves, Dante Rotili, Antonello Mai, Frank J Dekker
Lysine acetyltransferase 8 (KAT8) is a histone acetyltransferase (HAT) responsible for acetylating lysine 16 on histone H4 (H4K16) and plays a role in cell cycle progression as well as acetylation of the tumor suppressor protein p53. Further studies on its biological function and drug discovery initiatives will benefit from the development of small molecule inhibitors for this enzyme. As a first step towards this aim we investigated the enzyme kinetics of this bi-substrate enzyme. The kinetic experiments indicate a ping-pong mechanism in which the enzyme binds Ac-CoA first, followed by binding of the histone substrate...
November 13, 2015: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26387537/mof-maintains-transcriptional-programs-regulating-cellular-stress-response
#18
B N Sheikh, W Bechtel-Walz, J Lucci, O Karpiuk, I Hild, B Hartleben, J Vornweg, M Helmstädter, A H Sahyoun, V Bhardwaj, T Stehle, S Diehl, O Kretz, A K Voss, T Thomas, T Manke, T B Huber, A Akhtar
MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions...
May 2016: Oncogene
https://www.readbyqxmd.com/read/26306646/the-koolen-de-vries-syndrome-a-phenotypic-comparison-of-patients-with-a-17q21-31-microdeletion-versus-a-kansl1-sequence-variant
#19
David A Koolen, Rolph Pfundt, Katrin Linda, Gea Beunders, Hermine E Veenstra-Knol, Jessie H Conta, Ana Maria Fortuna, Gabriele Gillessen-Kaesbach, Sarah Dugan, Sara Halbach, Omar A Abdul-Rahman, Heather M Winesett, Wendy K Chung, Marguerite Dalton, Petia S Dimova, Teresa Mattina, Katrina Prescott, Hui Z Zhang, Howard M Saal, Jayne Y Hehir-Kwa, Marjolein H Willemsen, Charlotte W Ockeloen, Marjolijn C Jongmans, Nathalie Van der Aa, Pinella Failla, Concetta Barone, Emanuela Avola, Alice S Brooks, Sarina G Kant, Erica H Gerkes, Helen V Firth, Katrin Õunap, Lynne M Bird, Diane Masser-Frye, Jennifer R Friedman, Modupe A Sokunbi, Abhijit Dixit, Miranda Splitt, Mary K Kukolich, Julie McGaughran, Bradley P Coe, Jesús Flórez, Nael Nadif Kasri, Han G Brunner, Elizabeth M Thompson, Jozef Gecz, Corrado Romano, Evan E Eichler, Bert B A de Vries
The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies...
May 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/26045981/status-of-epigenetic-chromatin-modification-enzymes-and-esophageal-squamous-cell-carcinoma-risk-in-northeast-indian-population
#20
Virendra Singh, Laishram C Singh, Avninder P Singh, Jagannath Sharma, Bibhuti B Borthakur, Arundhati Debnath, Avdhesh K Rai, Rup K Phukan, Jagadish Mahanta, Amal C Kataki, Sujala Kapur, Sunita Saxena
Esophageal cancer incidence is reported in high frequency in northeast India. The etiology is different from other population at India due to wide variations in dietary habits or nutritional factors, tobacco/betel quid chewing and alcohol habits. Since DNA methylation, histone modification and miRNA-mediated epigenetic processes alter the gene expression, the involvement of these processes might be useful to find out epigenetic markers of esophageal cancer risk in northeast Indian population. The present investigation was aimed to carryout differential expression profiling of chromatin modification enzymes in tumor and normal tissue collected from esophageal squamous cell carcinoma (ESCC) patients...
2015: American Journal of Cancer Research
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