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Chromatin modulation

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https://www.readbyqxmd.com/read/28722470/novel-potent-inhibitors-of-the-histone-demethylase-kdm1a-lsd1-orally-active-in-a-murine-promyelocitic-leukemia-model
#1
Paolo Trifirò, Anna Cappa, Silvia Brambillasca, Oronza A Botrugno, Maria Rosaria Cera, Roberto Dal Zuffo, Paola Dessanti, Giuseppe Meroni, Florian Thaler, Manuela Villa, Saverio Minucci, Ciro Mercurio, Mario Varasi, Paola Vianello
BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor...
July 19, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28718414/epigenetics-and-cancer-stem-cells-unleashing-hijacking-and-restricting-cellular-plasticity
#2
REVIEW
Elanor N Wainwright, Paola Scaffidi
Epigenetic mechanisms have emerged as key players in cancer development which affect cellular states at multiple stages of the disease. During carcinogenesis, alterations in chromatin and DNA methylation resulting from genetic lesions unleash cellular plasticity and favor oncogenic cellular reprogramming. At later stages, during cancer growth and progression, additional epigenetic changes triggered by interaction with the microenvironment modulate cancer cell phenotypes and properties, and shape tumor architecture...
May 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28717873/orchestration-of-h3k27-methylation-mechanisms-and-therapeutic-implication
#3
REVIEW
Mei-Ren Pan, Ming-Chuan Hsu, Li-Tzong Chen, Wen-Chun Hung
Histone proteins constitute the core component of the nucleosome, the basic unit of chromatin. Chemical modifications of histone proteins affect their interaction with genomic DNA, the accessibility of recognized proteins, and the recruitment of enzymatic complexes to activate or diminish specific transcriptional programs to modulate cellular response to extracellular stimuli or insults. Methylation of histone proteins was demonstrated 50 years ago; however, the biological significance of each methylated residue and the integration between these histone markers are still under intensive investigation...
July 17, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28717195/stability-of-the-phf10-subunit-of-pbaf-signature-module-is-regulated-by-phosphorylation-role-of-%C3%AE-trcp
#4
Victor V Tatarskiy, Yuriy P Simonov, Dmitrii S Shcherbinin, Alexander V Brechalov, Sofia G Georgieva, Nataliya V Soshnikova
The PBAF chromatin-remodeling complexes are multi-protein machines, regulating expression of genes involved in proliferation and differentiation. PHF10 is a subunit of the PBAF essential for its association with chromatin. Mammalian PHF10 is expressed as four ubiquitous isoforms, which are alternatively incorporated in the complex and differ by their influence on transcription of target genes. PHF10 have different domain structure and two of them (PHF10-S isoforms) lack C-terminal PHD domains, which enables their phosphorylation by CK-1...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716910/methylcytosine-dioxygenase-tet3-interacts-with-thyroid-hormone-nuclear-receptors-and-stabilizes-their-association-to-chromatin
#5
Wenyue Guan, Romain Guyot, Jacques Samarut, Frédéric Flamant, Jiemin Wong, Karine Cécile Gauthier
Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. Here we identified the ten-eleven translocation protein 3 (TET3) as a TR interacting protein increasing cell sensitivity to T3. The interaction between TET3 and TRs is independent of TET3 catalytic activity and specifically allows the stabilization of TRs on chromatin. We provide evidence that TET3 is required for TR stability, efficient binding of target genes, and transcriptional activation...
July 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28715484/multiple-renal-cancer-susceptibility-polymorphisms-modulate-the-hif-pathway
#6
Steffen Grampp, Virginia Schmid, Rafik Salama, Victoria Lauer, Franziska Kranz, James L Platt, James Smythies, Hani Choudhry, Margarete Goppelt-Struebe, Peter J Ratcliffe, David R Mole, Johannes Schödel
Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12...
July 17, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28714688/design-of-a-chemical-probe-for-the-bromodomain-and-plant-homeodomain-finger-containing-brpf-family-of-proteins
#7
Niall Igoe, Elliott D Bayle, Cynthia Tallant, Oleg Fedorov, Julia C Meier, Pavel Savitsky, Catherine Rogers, Yannick Morias, Sarah Scholze, Helen Boyd, Danen Cunoosamy, David M Andrews, Anne Cheasty, Paul E Brennan, Susanne Müller, Stefan Knapp, Paul V Fish
The bromodomain and PHD finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRD1 over BRPF3, whereas binding to BRD9 was weaker. 16 has excellent selectivity over non-class IV BRD proteins. Target engagement of BRPF1B and BRD1 with 16 was demonstrated in nanoBRET and FRAP assays...
July 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28712876/drosophila-sce-dring-e3-ligase-inhibits-apoptosis-in-a-dp53-dependent-manner
#8
Rocío Simón, Carolina J Simoes da Silva, Sol Fereres, Ana Busturia
The Polycomb group (PcG) of proteins control developmental gene silencing and are highly conserved between flies and mammals. PcG proteins function by controlling post-translational modification of histones, such as ubiquitylation, which impacts chromatin compaction and thus gene transcription. Changes in PcG cellular levels have drastic effects on organismal development and are involved in the generation of human pathologies such as cancer. However, the mechanisms controlling their levels of expression and their physiological effects are only partially understood...
July 13, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28711634/role-of-epigenetic-modulation-in-cancer-stem-cell-fate
#9
REVIEW
Abhijeet Deshmukh, Mudra Binju, Frank Arfuso, Philip Newsholme, Arun Dharmarajan
A sub-population of the tumor micro-environment consists of cancer stem cells (CSCs), which are responsible for the initiation and recurrence of cancer. Recently, epigenetic processes such as DNA methylation, histone modification, and chromatin remodelling have been found to be involved in inducing epigenetic factors in CSCs. Most of these processes, such as DNA methylation, generally occur in the genome that is rich in Cytosine-Guanine repeat sequences, also known as CpG islands, which are distributed throughout the human genome...
July 12, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28704214/bile-acids-upregulate-brca1-and-downregulate-estrogen-receptor-1-gene-expression-in-ovarian-cancer-cells
#10
Qunyan Jin, Olivier Noel, Mai Nguyen, Lionel Sam, Glenn S Gerhard
Two major risk factors for ovarian cancer include loss-of-function mutations in the BRCA1 (breast cancer 1, early onset) gene and aspects of estrogen metabolism. Modulation of the levels of the normal BRCA1 allele and estrogen receptor expression may therefore be a preventive strategy. Consensus binding motifs for the bile acid-responsive transcription factor farnesoid X receptor were identified in the BRCA1 and estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) genes, supported by chromatin immunoprecipitation sequencing data...
July 12, 2017: European Journal of Cancer Prevention
https://www.readbyqxmd.com/read/28703221/manipulation-of-nuclear-architecture-through-crispr-mediated-chromosomal-looping
#11
Stefanie L Morgan, Natasha C Mariano, Abel Bermudez, Nicole L Arruda, Fangting Wu, Yunhai Luo, Gautam Shankar, Lin Jia, Huiling Chen, Ji-Fan Hu, Andrew R Hoffman, Chiao-Chain Huang, Sharon J Pitteri, Kevin C Wang
Chromatin looping is key to gene regulation, yet no broadly applicable methods to selectively modify chromatin loops have been described. We have engineered a method for chromatin loop reorganization using CRISPR-dCas9 (CLOuD9) to selectively and reversibly establish chromatin loops. We demonstrate the power of this technology to selectively modulate gene expression at targeted loci.
July 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28701767/actomyosin-and-vimentin-cytoskeletal-networks-regulate-nuclear-shape-mechanics-and-chromatin-organization
#12
Michael C Keeling, Luis R Flores, Asad H Dodhy, Elizabeth R Murray, Núria Gavara
The regulation of nuclear state by the cytoskeleton is an important part of cellular function. Actomyosin stress fibres, microtubules and intermediate filaments have distinct and complementary roles in integrating the nucleus into its environment and influencing its mechanical state. However, the interconnectedness of cytoskeletal networks makes it difficult to dissect their individual effects on the nucleus. We use simple image analysis approaches to characterize nuclear state, estimating nuclear volume, Poisson's ratio, apparent elastic modulus and chromatin condensation...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701701/systematic-discovery-of-genetic-modulation-by-jumonji-histone-demethylases-in-drosophila
#13
Nevine A Shalaby, Raheel Sayed, Qiao Zhang, Shane Scoggin, Susan Eliazer, Adrian Rothenfluh, Michael Buszczak
Jumonji (JmjC) domain proteins influence gene expression and chromatin organization by way of histone demethylation, which provides a means to regulate the activity of genes across the genome. JmjC proteins have been associated with many human diseases including various cancers, developmental and neurological disorders, however, the shared biology and possible common contribution to organismal development and tissue homeostasis of all JmjC proteins remains unclear. Here, we systematically tested the function of all 13 Drosophila JmjC genes...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701698/global-mapping-of-the-macrophage-hiv-1-transcriptome-reveals-that-productive-infection-induces-remodeling-of-host-cell-dna-and-chromatin
#14
Alexandre Deshiere, Charles Joly-Beauparlant, Yann Breton, Michel Ouellet, Frédéric Raymond, Robert Lodge, Corinne Barat, Marc-André Roy, Jacques Corbeil, Michel J Tremblay
It has been proposed that macrophages could serve as long-lived compartments for HIV-1 infection under in vivo situations because these cells are resistant to the virus-mediated cytopathic effect, produce progeny virus over extended periods of time and are localized in tissues that are often less accessible by treatment. Comprehensive experimental studies are thus needed to characterize the HIV-1-induced modulation of host genes in these myeloid lineage cells. To shed light on this important issue, we performed comparative analyses of mRNA expression levels of host genes in uninfected bystander and HIV-1-infected human macrophages using an infectious reporter virus construct coupled with a large-scale RNA sequencing approach...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696859/nucleoporins-redistribute-inside-the-nucleus-after-cell-cycle-arrest-induced-by-histone-deacetylases-inhibition
#15
Miguel Pérez-Garrastachu, Jon Arluzea, Ricardo Andrade, Alejandro Díez-Torre, Marta Urtizberea, Margarita Silió, Juan Aréchaga
Nucleoporins are the main components of the nuclear-pore complex (NPC) and were initially considered as mere structural elements embedded in the nuclear envelope, being responsible for nucleocytoplasmic transport. Nevertheless, several recent scientific reports have revealed that some nucleoporins participate in nuclear processes such as transcription, replication, DNA repair and chromosome segregation. Thus, the interaction of NPCs with chromatin could modulate the distribution of chromosome territories relying on the epigenetic state of DNA...
July 11, 2017: Nucleus
https://www.readbyqxmd.com/read/28696245/the-histone-codes-for-meiosis
#16
REVIEW
Lina Wang, Zhiliang Xu, Muhammad Babar Khawar, Chao Liu, Wei Li
Meiosis is a specialized process that produces haploid gametes from diploid cells by a single round of DNA replication followed by two successive cell divisions. It contains many special events, such as programmed DNA double-strand break (DSB) formation, homologous recombination, crossover formation and resolution. These events are associated with dynamically regulated chromosomal structures, the dynamic transcriptional regulation and chromatin remodeling are mainly modulated by histone modifications, termed 'histone codes'...
September 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28695510/poly-adp-ribose-dependent-chromatin-remodeling-in-dna-repair
#17
Théo Lebeaupin, Rebecca Smith, Sébastien Huet, Gyula Timinszky
The tightly packed and dynamic structure of chromatin can undergo major reorganization in response to endogenous or exogenous stimuli, such as the regulation of transcription or the cell cycle, or following DNA damage. A fast and local chromatin decondensation is observed upon DNA damage induced by laser micro-irradiation. This decondensation is under the control of poly(ADP-ribosyl)ation (PARylation) by PARP1, one of the first proteins recruited at the DNA damage sites. This chapter provides a step-by-step guide to perform and analyze chromatin decondensation upon DNA damage induction...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28694783/mpa-modulates-tight-junctions-permeability-via-midkine-pi3k-pathway-in-caco-2-cells-a-possible-mechanism-of-leak-flux-diarrhea-in-organ-transplanted-patients
#18
Niamat Khan, Lutz Binder, D V Krishna Pantakani, Abdul R Asif
Mycophenolic acid (MPA) is prescribed to prevent allograft rejection in organ transplanted patients. However, its use is sporadically linked to leak flux diarrhea and other gastrointestinal (GI) disturbances in around 75% of patients through yet unknown mechanisms. Recently, we identified Midkine as a modulator of tight junctions (TJs) permeability in MPA treated Caco-2 monolayer. In the present study, we investigated the possible involvement of Midkine dependent PI3K pathway in alteration of TJs under MPA treatment...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28692904/emerging-roles-of-the-histone-chaperone-caf-1-in-cellular-plasticity
#19
REVIEW
Sihem Cheloufi, Konrad Hochedlinger
During embryonic development, cells become progressively restricted in their differentiation potential. This is thought to be regulated by dynamic changes in chromatin structure and associated modifications, which act together to stabilize distinct specialized cell lineages. Remarkably, differentiated cells can be experimentally reprogrammed to a stem cell-like state or to alternative lineages. Thus, cellular reprogramming provides a valuable platform to study the mechanisms that normally safeguard cell identity and uncover factors whose manipulation facilitates cell fate transitions...
July 7, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28689197/nkl-homeobox-gene-msx1-acts-like-a-tumor-suppressor-in-nk-cell-leukemia
#20
Stefan Nagel, Claudia Pommerenke, Corinna Meyer, Maren Kaufmann, Roderick A F MacLeod, Hans G Drexler
NKL homeobox gene MSX1 is physiologically expressed in lymphoid progenitors and subsequently downregulated in developing T- and B-cells. In contrast, elevated expression levels of MSX1 persist in mature natural killer (NK)-cells, indicating a functional role in this compartment. While T-cell acute lymphoblastic leukemia (T-ALL) subsets exhibit aberrant overexpression of MSX1, we show here that in malignant NK-cells the level of MSX1 transcripts is aberrantly downregulated. Chromosomal deletions at 4p16 hosting the MSX1 locus have been described in NK-cell leukemia patients...
June 21, 2017: Oncotarget
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