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https://www.readbyqxmd.com/read/28630052/infection-exposure-promotes-etv6-runx1-precursor-b-cell-leukemia-via-impaired-h3k4-demethylases
#1
Guillermo Rodríguez-Hernández, Julia Hauer, Alberto Martín-Lorenzo, Daniel Schäfer, Christoph Bartenhagen, Idoia García-Ramírez, Franziska Auer, Ines Gonzalez-Herrero, Lucia Ruiz-Roca, Michael Gombert, Vera Okpanyi, Ute Fischer, Cai Chen, Martin Dugas, Sanil Bhatia, René M Linka, Marta Garcia-Suquia, María V Rascón-Trincado, Angel Garcia-Sanchez, Oscar Blanco, Maria Begona Garcia-Cenador, Francisco Javier Garcia-Criado, César Cobaleda, Diego Alonso-López, Javier De Las Rivas, Markus Müschen, Carolina Vicente-Dueñas, Isidro Sánchez-García, Arndt Borkhardt
<p>ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/peripheral cells (HSC/PC) and postnatal infections for human-like pB-ALL...
June 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/28548959/identification-of-the-histone-lysine-demethylase-kdm4a-jmjd2a-as-a-novel-epigenetic-target-in-m1-macrophage-polarization-induced-by-oxidized-ldl
#2
Xue Wang, Siqing Wang, Gang Yao, Dehai Yu, Kexin Chen, Qian Tong, Long Ye, Chuan Wu, Yue Sun, Haixia Li, Dirk M Hermann, Thorsten R Doeppner, Fengyan Jin, Yun Dai, Jiang Wu
Oxidized low density lipoprotein (oxLDL) induces macrophage activation, an event essential for atherosclerosis. Emerging evidence supports that epigenetic regulation plays important roles in macrophage activation and function. However, it remains unclear which epigenetic modulator is responsible for oxLDL-induced macrophage activation. Here, we identify for the first time KDM4A (JMJD2A) as an epigenetic modifying enzyme that controls oxLDL-induced pro-inflammatory M1 polarization of macrophages. OxLDL triggered M1 polarization of murine and human macrophages, characterized by expression of iNOS and robust production of inflammatory cytokines (e...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28546743/common-methods-of-biological-age-estimation
#3
REVIEW
Linpei Jia, Weiguang Zhang, Xiangmei Chen
At present, no single indicator could be used as a golden index to estimate aging process. The biological age (BA), which combines several important biomarkers with mathematical modeling, has been proposed for >50 years as an aging estimation method to replace chronological age (CA). The common methods used for BA estimation include the multiple linear regression (MLR), the principal component analysis (PCA), the Hochschild's method, and the Klemera and Doubal's method (KDM). The fundamental differences in these four methods are the roles of CA and the selection criteria of aging biomarkers...
2017: Clinical Interventions in Aging
https://www.readbyqxmd.com/read/28432280/small-molecules-targeting-histone-demethylase-genes-kdms-inhibit-growth-of-temozolomide-resistant-glioblastoma-cells
#4
Barbara Banelli, Antonio Daga, Alessandra Forlani, Giorgio Allemanni, Daniela Marubbi, Maria Pia Pistillo, Aldo Profumo, Massimo Romani
In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as "epigenetic resilience". We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy.We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28346812/identification-of-a-novel-benzimidazole-pyrazolone-scaffold-that-inhibits-kdm4-lysine-demethylases-and-reduces-proliferation-of-prostate-cancer-cells
#5
David M Carter, Edgar Specker, Jessica Przygodda, Martin Neuenschwander, Jens Peter von Kries, Udo Heinemann, Marc Nazaré, Ulrich Gohlke
Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment...
March 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28265301/assessing-histone-demethylase-inhibitors-in-cells-lessons-learned
#6
Stephanie B Hatch, Clarence Yapp, Raquel C Montenegro, Pavel Savitsky, Vicki Gamble, Anthony Tumber, Gian Filippo Ruda, Vassilios Bavetsias, Oleg Fedorov, Butrus Atrash, Florence Raynaud, Rachel Lanigan, LeAnne Carmichael, Kathy Tomlin, Rosemary Burke, Susan M Westaway, Jack A Brown, Rab K Prinjha, Elisabeth D Martinez, Udo Oppermann, Christopher J Schofield, Chas Bountra, Akane Kawamura, Julian Blagg, Paul E Brennan, Olivia Rossanese, Susanne Müller
BACKGROUND: Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active 'probe' molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28110151/selection-of-an-optimal-set-of-biomarkers-and-comparative-analyses-of-biological-age-estimation-models-in-korean-females
#7
Haemi Jee, Jaehyun Park
To date, an optimal working model which predicts biological age (BA) with a set of working biomarkers has not been devised to represent the Korean female population. Accuracy of prediction and applicability are required of an optimal set of commonly assessed biomarkers to provide information on the health status. The goal of this study was to identify a set of biomarkers that represent the aging process and to develop and compare different BA prediction models to elucidate the most fitting and applicable model for providing information on health status in the Korean female population...
May 2017: Archives of Gerontology and Geriatrics
https://www.readbyqxmd.com/read/27819678/tet2-binds-the-androgen-receptor-and-loss-is-associated-with-prostate-cancer
#8
M L Nickerson, S Das, K M Im, S Turan, S I Berndt, H Li, H Lou, S A Brodie, J N Billaud, T Zhang, A J Bouk, D Butcher, Z Wang, L Sun, K Misner, W Tan, A Esnakula, D Esposito, W Y Huang, R N Hoover, M A Tucker, J R Keller, J Boland, K Brown, S K Anderson, L E Moore, W B Isaacs, S J Chanock, M Yeager, M Dean, T Andresson
Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2...
April 2017: Oncogene
https://www.readbyqxmd.com/read/27800026/hypoxia-increases-genome-wide-bivalent-epigenetic-marking-by-specific-gain-of-h3k27me3
#9
Peggy Prickaerts, Michiel E Adriaens, Twan van den Beucken, Elizabeth Koch, Ludwig Dubois, Vivian E H Dahlmans, Caroline Gits, Chris T A Evelo, Michelle Chan-Seng-Yue, Bradly G Wouters, Jan Willem Voncken
BACKGROUND: Trimethylation at histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) controls gene activity during development and differentiation. Whether H3K4me3 and H3K27me3 changes dynamically in response to altered microenvironmental conditions, including low-oxygen conditions commonly present in solid tumors, is relatively unknown. Demethylation of H3K4me3 and H3K27me3 is mediated by oxygen and 2-oxoglutarate dioxygenases enzymes, suggesting that oxygen deprivation (hypoxia) may influence histone trimethylation...
2016: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/27739832/quantum-signature-of-chaos-and-thermalization-in-the-kicked-dicke-model
#10
S Ray, A Ghosh, S Sinha
We study the quantum dynamics of the kicked Dicke model (KDM) in terms of the Floquet operator, and we analyze the connection between chaos and thermalization in this context. The Hamiltonian map is constructed by suitably taking the classical limit of the Heisenberg equation of motion to study the corresponding phase-space dynamics, which shows a crossover from regular to chaotic motion by tuning the kicking strength. The fixed-point analysis and calculation of the Lyapunov exponent (LE) provide us with a complete picture of the onset of chaos in phase-space dynamics...
September 2016: Physical Review. E
https://www.readbyqxmd.com/read/27732873/systematic-analysis-of-known-and-candidate-lysine-demethylases-in-the-regulation-of-myoblast-differentiation
#11
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics plays a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic and functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here, we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
June 30, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27696458/iron-acquisition-and-siderophore-production-in-the-fish-pathogen-renibacterium-salmoninarum
#12
J Bethke, M Poblete-Morales, R Irgang, A Yáñez, R Avendaño-Herrera
Renibacterium salmoninarum is the causative agent of bacterial kidney disease, which significantly affects salmonid farming worldwide. Despite this impact, there is scarce data on its iron uptake ability, a factor of pathogenesis. This study investigated the iron acquisition mechanisms of R. salmoninarum and its capacity to uptake iron from different sources. Thirty-two Chilean isolates and the DSM20767(T) type strain grew in the presence of 2,2'-Dipyridyl at varying concentrations (250-330 μm), and all isolates positively reacted on chrome azurol S agar...
November 2016: Journal of Fish Diseases
https://www.readbyqxmd.com/read/27532610/low-physical-activity-and-its-association-with-diabetes-and-other-cardiovascular-risk-factors-a-nationwide-population-based-study
#13
Laura Brugnara, Serafín Murillo, Anna Novials, Gemma Rojo-Martínez, Federico Soriguer, Albert Goday, Alfonso Calle-Pascual, Luis Castaño, Sonia Gaztambide, Sergio Valdés, Josep Franch, Conxa Castell, Joan Vendrell, Roser Casamitjana, Anna Bosch-Comas, Elena Bordiú, Rafael Carmena, Miguel Catalá, Elias Delgado, Juan Girbés, Alfonso López-Alba, Maria Teresa Martínez-Larrad, Edelmiro Menéndez, Inmaculada Mora-Peces, Gemma Pascual-Manich, Manuel Serrano-Ríos, Ramon Gomis, Emilio Ortega
Low physical activity (PA), or sedentary lifestyle, is associated with the development of several chronic diseases. We aimed to investigate current prevalence of sedentariness and its association with diabetes and other cardiovascular risk factors. PA was evaluated in a population-based, cross-sectional, randomly sampled study conducted in 2009-2010 in Spain. International Physical Activity Questionnaire (SF-IPAQ) was used to assess PA. 4991 individuals (median age 50 years, 57% women) were studied. Prevalence of sedentariness was 32...
2016: PloS One
https://www.readbyqxmd.com/read/27514027/epigenetic-gene-regulation-by-histone-demethylases-emerging-role-in-oncogenesis-and-inflammation
#14
M K Kang, S Mehrazarin, N-H Park, C-Y Wang
Histone N-terminal tails of nucleosomes are the sites of complex regulation of gene expression through post-translational modifications. Among these modifications, histone methylation had long been associated with permanent gene inactivation until the discovery of Lys-specific demethylase (LSD1), which is responsible for dynamic gene regulation. There are more than 30 members of the Lys demethylase (KDM) family, and with exception of LSD1 and LSD2, all other KDMs possess the Jumonji C (JmjC) domain exhibiting demethylase activity and require unique cofactors, for example, Fe(II) and α-ketoglutarate...
August 11, 2016: Oral Diseases
https://www.readbyqxmd.com/read/27458201/an-easy-and-efficient-inducible-crispr-cas9-platform-with-improved-specificity-for-multiple-gene-targeting
#15
Jian Cao, Lizhen Wu, Shang-Min Zhang, Min Lu, William K C Cheung, Wesley Cai, Molly Gale, Qi Xu, Qin Yan
The CRISPR/Cas9 system is a powerful genome editing tool and has been widely used for biomedical research. However, many challenges, such as off-target effects and lack of easy solutions for multiplex targeting, are still limiting its applications. To overcome these challenges, we first developed a highly efficient doxycycline-inducible Cas9-EGFP vector. This vector allowed us to track the cells for uniform temporal control and efficient gene disruption, even in a polyclonal setting. Furthermore, the inducible CRISPR/Cas9 system dramatically decreased off-target effects with a pulse exposure of the genome to the Cas9/sgRNA complex...
November 2, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27443988/suppressive-activity-of-a-viral-histone-h4-against-two-host-chromatin-remodelling-factors-lysine-demethylase-and-swi-snf
#16
Sunil Kumar, Prasad Venkata, Yonggyun Kim
Histone H4, a nucleosome subunit in eukaryotes, plays crucial roles in DNA package and regulation of gene expression through covalent modification. A viral histone H4 encoded in Cotesia plutellae bracovirus (CpBV), a polydnavirus, is called CpBV-H4. It is highly homologous to other histone H4 proteins excepting 38 extra amino acid residues in the N terminus. CpBV-H4 can form octamer with other histone subunits and alter host gene expression. In this study, CpBV-H4 was transiently expressed in a natural host (Plutella xylostella) and its suppressive activity on host gene expression was evaluated by the suppressive subtractive hybridization (SSH) technique...
October 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27372758/purification-biochemical-analysis-and-structure-determination-of-jmjc-lysine-demethylases
#17
S Krishnan, R C Trievel
Jumonji C (JmjC) lysine demethylases (KDMs) catalyze the site- and state-specific demethylation of lysine residues in histone and nonhistone protein substrates. These enzymes have been implicated in diverse genomic processes, including epigenetic gene regulation, DNA damage response, DNA replication, and regulation of heterochromatin structure. In addition, a number of JmjC KDMs contribute to the incidence of numerous cancers, rendering them targets for the development of novel chemotherapeutic drugs. Using the JMJD2 KDM subfamily as representative examples, this chapter outlines strategies for purifying highly active, recombinant JmjC KDMs lacking inhibitory transition metal ions, characterizing kinetic parameters of these enzymes using a coupled fluorescent assay, and determining crystal structures of the enzymes in complex with methylated histone peptides...
2016: Methods in Enzymology
https://www.readbyqxmd.com/read/27337104/arginine-demethylation-is-catalysed-by-a-subset-of-jmjc-histone-lysine-demethylases
#18
Louise J Walport, Richard J Hopkinson, Rasheduzzaman Chowdhury, Rachel Schiller, Wei Ge, Akane Kawamura, Christopher J Schofield
While the oxygen-dependent reversal of lysine N(ɛ)-methylation is well established, the existence of bona fide N(ω)-methylarginine demethylases (RDMs) is controversial. Lysine demethylation, as catalysed by two families of lysine demethylases (the flavin-dependent KDM1 enzymes and the 2-oxoglutarate- and oxygen-dependent JmjC KDMs, respectively), proceeds via oxidation of the N-methyl group, resulting in the release of formaldehyde. Here we report detailed biochemical studies clearly demonstrating that, in purified form, a subset of JmjC KDMs can also act as RDMs, both on histone and non-histone fragments, resulting in formaldehyde release...
June 23, 2016: Nature Communications
https://www.readbyqxmd.com/read/27295953/synthesis-and-characterisation-of-substrate-based-peptides-as-inhibitors-of-histone-demethylase-kdm4c
#19
Simon D Nielsen, Ulrike Leurs, Magnus Bergner, Silvia A Barris, Kanchan Devkota, Kamilla Meyer, Daniella Iaria, Jack McCaughan, Brian Lohse, Jesper L Kristensen, Rasmus P Clausen
The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N-acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors...
2016: Protein and Peptide Letters
https://www.readbyqxmd.com/read/27114850/hypoxia-inducible-histone-lysine-demethylases-impact-on-the-aging-process-and-age-related-diseases
#20
REVIEW
Antero Salminen, Kai Kaarniranta, Anu Kauppinen
Hypoxia is an environmental stress at high altitude and underground conditions but it is also present in many chronic age-related diseases, where blood flow into tissues is impaired. The oxygen-sensing system stimulates gene expression protecting tissues against hypoxic insults. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to e.g. enhanced energy metabolism and autophagy. Moreover, many stress-related signaling mechanisms, such as oxidative stress and energy metabolic disturbances, as well as the signaling cascades via ceramide, mTOR, NF-κB, and TGF-β pathways, can also induce the expression of HIF-1α protein to facilitate cell survival in normoxia...
March 2016: Aging and Disease
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