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https://www.readbyqxmd.com/read/29728365/a-crispr-knockout-screen-identifies-setdb1-target-retroelement-silencing-factors-in-embryonic-stem-cells
#1
Kei Fukuda, Akihiko Okuda, Kosuke Yusa, Yoichi Shinkai
In mouse embryonic stem cells (mESCs), expression of provirus and endogenous retroelements is epigenetically repressed. Although many cellular factors involved in retroelement silencing have been identified, the complete molecular mechanism remains elusive. In this study, we performed a genome-wide CRISPR screen to advance our understanding of retroelement silencing in mESCs. The Moloney murine leukemia virus (MLV)-based retroviral vector MSCV-GFP, which is repressed by the SETDB1/KAP1 pathway in mESCs was used as a reporter provirus and we identified more than 80 genes involved in this process...
May 4, 2018: Genome Research
https://www.readbyqxmd.com/read/29669285/kap1-regulates-regulatory-t-cell-function-and-proliferation-in-both-foxp3-dependent-and-independent-manners
#2
Shigeru Tanaka, Christian Pfleger, Jen-Feng Lai, Florence Roan, Shao-Cong Sun, Steven F Ziegler
Regulatory T cells (Tregs) are indispensable for the establishment of tolerance of self-antigens in animals. The transcriptional regulator Foxp3 is critical for Treg development and function, controlling the expression of genes important for Tregs through interactions with binding partners. We previously reported KAP1 as a binding partner of FOXP3 in human Tregs, but the mechanisms by which KAP1 affects Treg function were unclear. In this study, we analyzed mice with Treg-specific deletion of KAP1 and found that they develop spontaneous autoimmune disease...
April 17, 2018: Cell Reports
https://www.readbyqxmd.com/read/29661885/the-long-non-coding-rna-paupar-promotes-kap1-dependent-chromatin-changes-and-regulates-olfactory-bulb-neurogenesis
#3
Ioanna Pavlaki, Farah Alammari, Bin Sun, Neil Clark, Tamara Sirey, Sheena Lee, Dan J Woodcock, Chris P Ponting, Francis G Szele, Keith W Vance
Many long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their in vivo roles and mechanisms of action remain poorly understood. Paupar , a CNS-expressed lncRNA, controls neuroblastoma cell growth by binding and modulating the activity of transcriptional regulatory elements in a genome-wide manner. We show here that the Paupar lncRNA directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation...
April 16, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29610526/zinc-finger-protein-471-suppresses-gastric-cancer-through-transcriptionally-repressing-downstream-oncogenic-pls3-and-tfap2a
#4
Lei Cao, Shiyan Wang, Yanquan Zhang, Ka-Chun Wong, Geicho Nakatsu, Xiaohong Wang, Sunny Wong, Jiafu Ji, Jun Yu
Zinc-finger protein 471 (ZNF471) was preferentially methylated in gastric cancer using promoter methylation array. The role of ZNF471 in human cancer is unclear. Here we elucidated the functional significance, molecular mechanisms and clinical impact of ZNF471 in gastric cancer. ZNF471 mRNA was silenced in 15 out of 16 gastric cancer cell lines due to promoter hypermethylation. Significantly higher ZNF471 promoter methylation was also observed in primary gastric cancers compared to their adjacent normal tissues (P < 0...
April 3, 2018: Oncogene
https://www.readbyqxmd.com/read/29581310/adeno-associated-virus-rep-proteins-antagonize-phosphatase-pp1-to-counteract-kap1-repression-of-the-latent-viral-genome
#5
Sarah Smith-Moore, Stuart J D Neil, Cornel Fraefel, R Michael Linden, Mathieu Bollen, Helen M Rowe, Els Henckaerts
Adeno-associated virus (AAV) is a small human Dependovirus whose low immunogenicity and capacity for long-term persistence have led to its widespread use as vector for gene therapy. Despite great recent successes in AAV-based gene therapy, further improvements in vector technology may be hindered by an inadequate understanding of various aspects of basic AAV biology. AAV is unique in that its replication is largely dependent on a helper virus and cellular factors. In the absence of helper virus coinfection, wild-type AAV establishes latency through mechanisms that are not yet fully understood...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29482634/individual-retrotransposon-integrants-are-differentially-controlled-by-kzfp-kap1-dependent-histone-methylation-dna-methylation-and-tet-mediated-hydroxymethylation-in-na%C3%A3-ve-embryonic-stem-cells
#6
Andrea Coluccio, Gabriela Ecco, Julien Duc, Sandra Offner, Priscilla Turelli, Didier Trono
BACKGROUND: The KZFP/KAP1 (KRAB zinc finger proteins/KRAB-associated protein 1) system plays a central role in repressing transposable elements (TEs) and maintaining parent-of-origin DNA methylation at imprinting control regions (ICRs) during the wave of genome-wide reprogramming that precedes implantation. In naïve murine embryonic stem cells (mESCs), the genome is maintained highly hypomethylated by a combination of TET-mediated active demethylation and lack of de novo methylation, yet KAP1 is tethered by sequence-specific KZFPs to ICRs and TEs where it recruits histone and DNA methyltransferases to impose heterochromatin formation and DNA methylation...
February 26, 2018: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/29444892/role-of-protein-phosphatase-1-and-inhibitor-of-protein-phosphatase-1-in-nitric-oxide-dependent-inhibition-of-the-dna-damage-response-in-pancreatic-%C3%AE-cells
#7
Bryndon J Oleson, Aaron Naatz, Sarah C Proudfoot, Chay Teng Yeo, John A Corbett
Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promote β-cell survival. We have shown that nitric oxide, in a cell type-selective manner, inhibits the DNA damage response (DDR) and, in doing so, protects β-cells from DNA damage-induced apoptosis. This study explores potential mechanisms by which nitric oxide inhibits DDR signaling. We show that inhibition of DDR signaling (measured by γH2AX formation and the phosphorylation of KAP1) is selective for nitric oxide, as other forms of reactive oxygen/nitrogen species do not impair DDR signaling...
May 2018: Diabetes
https://www.readbyqxmd.com/read/29357389/interferon-regulatory-factor-8-regulates-caspase-1-expression-to-facilitate-epstein-barr-virus-reactivation-in-response-to-b-cell-receptor-stimulation-and-chemical-induction
#8
Dong-Wen Lv, Kun Zhang, Renfeng Li
Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a transcription factor of the IRF family. IRF8 plays a key role in normal B cell differentiation, a cellular process that is intrinsically associated with Epstein-Barr virus (EBV) reactivation. However, whether IRF8 regulates EBV lytic replication remains unknown. In this study, we utilized a CRISPR/Cas9 genomic editing approach to deplete IRF8 and found that IRF8 depletion dramatically inhibits the reactivation of EBV upon lytic induction...
January 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29284678/the-cue1-domain-of-the-snf2-like-chromatin-remodeler-smarcad1-mediates-its-association-with-krab-associated-protein-1-kap1-and-kap1-target-genes
#9
Dong Ding, Philipp Bergmaier, Parysatis Sachs, Marius Klangwart, Tamina Rückert, Nora Bartels, Jeroen Demmers, Mike Dekker, Raymond A Poot, Jacqueline E Mermoud
Chromatin in embryonic stem cells (ESCs) differs markedly from that in somatic cells, with ESCs exhibiting a more open chromatin configuration. Accordingly, ATP-dependent chromatin remodeling complexes are important regulators of ESC homeostasis. Depletion of the remodeler SMARCAD1, an ATPase of the SNF2 family, has been shown to affect stem cell state, but the mechanistic explanation for this effect is unknown. Here, we set out to gain further insights into the function of SMARCAD1 in mouse ESCs. We identified KRAB-associated protein 1 (KAP1) as the stoichiometric binding partner of SMARCAD1 in ESCs...
February 23, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29151149/impact-of-xist-rna-on-chromatin-modifications-and-transcriptional-silencing-maintenance-at-different-stages-of-imprinted-x-chromosome-inactivation-in-vole-microtus-levis
#10
Alexander I Shevchenko, Elena V Grigor'eva, Sergey P Medvedev, Irina S Zakharova, Elena V Dementyeva, Eugeny A Elisaphenko, Anastasia A Malakhova, Sophia V Pavlova, Suren M Zakian
In vole Microtus levis, cells of preimplantation embryo and extraembryonic tissues undergo imprinted X chromosome inactivation (iXCI) which is triggered by a long non-coding nuclear RNA, Xist. At early stages of iXCI, chromatin of vole inactive X chromosome is enriched with the HP1 heterochromatin-specific protein, trimethylated H3K9 and H4K20 attributable to constitutive heterochromatin. In the study, using vole trophoblast stem (TS) cells as a model of iXCI, we further investigated chromatin of the inactive X chromosome of M...
March 2018: Chromosoma
https://www.readbyqxmd.com/read/29138338/correction-for-gjyshi-et-al-activated-nrf2-interacts-with-kaposi-s-sarcoma-associated-herpesvirus-latency-protein-lana-1-and-host-protein-kap1-to-mediate-global-lytic-gene-repression
#11
Olsi Gjyshi, Arunava Roy, Sujoy Dutta, Mohanan Valiya Veettil, Dipanjan Dutta, Bala Chandran
No abstract text is available yet for this article.
December 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28884410/an-7-a-butyric-acid-prodrug-sensitizes-cutaneous-t-cell-lymphoma-cell-lines-to-doxorubicin-via-inhibition-of-dna-double-strand-breaks-repair
#12
Lilach Moyal, Neta Goldfeiz, Batia Gorovitz, Ada Rephaeli, Efrat Tal, Nataly Tarasenko, Abraham Nudelman, Yael Ziv, Emmilia Hodak
We previously found that the novel histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) had greater selectivity against cutaneous T-cell lymphoma (CTCL) than SAHA. AN-7 synergizes with doxorubicin (Dox), an anthracycline antibiotic that induces DNA breaks. This study aimed to elucidate the mechanism underlying the effect of AN-7 on Dox-induced double-strand DNA breaks (DSBs) in CTCL, MyLa and Hut78 cell lines. The following markers/assays were employed: comet assay; western blot of γH2AX and p-KAP1; immunofluorescence of γH2AX nuclear foci; Western blot of repair protein; quantification of DSBs-repair through homologous recombination...
February 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/28765213/krab-zinc-finger-proteins
#13
REVIEW
Gabriela Ecco, Michael Imbeault, Didier Trono
Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are the largest family of transcriptional regulators in higher vertebrates. Characterized by an N-terminal KRAB domain and a C-terminal array of DNA-binding zinc fingers, they participate, together with their co-factor KAP1 (also known as TRIM28), in repression of sequences derived from transposable elements (TEs). Until recently, KRAB-ZFP/KAP1-mediated repression of TEs was thought to lead to irreversible silencing, and the evolutionary selection of KRAB-ZFPs was considered to be just the host component of an arms race against TEs...
August 1, 2017: Development
https://www.readbyqxmd.com/read/28763864/-high-expression-of-hnrnpab-kap1-together-promote-poor-prognosis-in-hcc
#14
Z J Zhou, X Y Wang, X Y Xu, Z Q Hu, E B Chen, S L Zhou, W Z Wu, J Zhou, J Fan, Z Dai
Objective: To further understand the interaction protein spectrum of heterogeneous ribonucleoprotein AB (hnRNP AB), and to investigate their clinical significance in hepatocellular carcinoma (HCC). Methods: We carried out mass spectrometry to reveal the specific peptides of KRAB-associated protein 1 (Kap1) and hnRNPAB, and verified their interaction by immunocoprecipitation and western blotting. Expression of hnRNPAB/Kap1 proteins were detected by immunohistochemical staining in the tissue microarrays. Categorical data were analyzed by the chi square test or Fisher exact test; enumeration data between groups were compared using Student t-test or Wilcocon signed rank test; the cumulative recurrence and survival rates were evaluated using the Kaplan-Meier method and the differences were assessed using the log-rank test...
June 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/28670441/znf300-tight-self-regulation-and-functioning-through-dna-methylation-and-histone-acetylation
#15
Feng-Juan Yan, Jingyi Fan, Zan Huang, Jun-Jian Zhang
BACKGROUND: Accumulating evidence demonstrates that the KRAB-ZNFs involve in various biological processes. As a typical member of KRAB-ZNFs, dysregulation of ZNF300 contributes to multiple pathologies such as leukemia and cancer. However, mechanisms underlying ZNF300 tight regulation and its pathophysiological function remain largely unknown. METHODS: The effect of ZNF300ZFR on gene transcriptional activity was measured by Dual luciferase reporter system. ChIP-PCR assay were performed to detect the enrichment of ZNF300 protein and H3K9Ac in the ZNF300 gene...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28648892/asciz-atmin-is-dispensable-for-atm-signaling-in-response-to-replication-stress
#16
Rui Liu, Ashleigh King, Nicolas C Hoch, Catherine Chang, Gemma L Kelly, Andrew J Deans, Jörg Heierhorst
The ATM kinase plays critical roles in the response to DNA double-strand breaks, and can also be activated by prolonged DNA replication blocks. It has recently been proposed that replication stress-dependent ATM activation is mediated by ASCIZ (also known as ATMIN, ZNF822), an essential developmental transcription factor. In contrast, we show here that ATM activation, and phosphorylation of its substrates KAP1, p53 and H2AX in response to the replication blocking agent aphidicolin was unaffected in both immortalized and primary ASCIZ/ATMIN-deficient murine embryonic fibroblasts compared to control cells...
September 2017: DNA Repair
https://www.readbyqxmd.com/read/28607002/atm-wip1-activities-at-chromatin-control-plk1-re-activation-to-determine-g2-checkpoint-duration
#17
Himjyot Jaiswal, Jan Benada, Erik Müllers, Karen Akopyan, Kamila Burdova, Tobias Koolmeister, Thomas Helleday, René H Medema, Libor Macurek, Arne Lindqvist
After DNA damage, the cell cycle is arrested to avoid propagation of mutations. Arrest in G2 phase is initiated by ATM-/ATR-dependent signaling that inhibits mitosis-promoting kinases such as Plk1. At the same time, Plk1 can counteract ATR-dependent signaling and is required for eventual resumption of the cell cycle. However, what determines when Plk1 activity can resume remains unclear. Here, we use FRET-based reporters to show that a global spread of ATM activity on chromatin and phosphorylation of ATM targets including KAP1 control Plk1 re-activation...
July 14, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28392109/compartmentalization-of-dna-damage-response-between-heterochromatin-and-euchromatin-is-mediated-by-distinct-h2a-histone-variants
#18
Zdravko J Lorković, Chulmin Park, Malgorzata Goiser, Danhua Jiang, Marie-Therese Kurzbauer, Peter Schlögelhofer, Frédéric Berger
DNA double-strand break (DSB) repair depends on the ataxia telangiectasia mutated (ATM) kinase that phosphorylates the conserved C-terminal SQ motif present in the histone variant H2A.X [1-7]. In constitutive heterochromatin of mammals, DSB repair is delayed and relies on phosphorylation of the proteins HP1 and KAP1 by ATM [2, 8-14]. However, KAP1 is not conserved in plants and the HP1-related protein Like-HP1 (LHP1) is not localized at constitutive heterochromatin [15], suggesting that in plants, alternative mechanisms could be responsible for repair of DSBs in heterochromatin...
April 24, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28334004/the-mouse-genome-displays-highly-dynamic-populations-of-krab-zinc-finger-protein-genes-and-related-genetic-units
#19
Annamaria Kauzlaric, Gabriela Ecco, Marco Cassano, Julien Duc, Michael Imbeault, Didier Trono
KRAB-containing poly-zinc finger proteins (KZFPs) constitute the largest family of transcription factors encoded by mammalian genomes, and growing evidence indicates that they fulfill functions critical to both embryonic development and maintenance of adult homeostasis. KZFP genes underwent broad and independent waves of expansion in many higher vertebrates lineages, yet comprehensive studies of members harbored by a given species are scarce. Here we present a thorough analysis of KZFP genes and related units in the murine genome...
2017: PloS One
https://www.readbyqxmd.com/read/28327001/autophagy-promotes-the-repair-of-radiation-induced-dna-damage-in-bone-marrow-hematopoietic-cells-via-enhanced-stat3-signaling
#20
Fei Xu, Xin Li, Lili Yan, Na Yuan, Yixuan Fang, Yan Cao, Li Xu, Xiaoying Zhang, Lan Xu, Chaorong Ge, Ni An, Gaoyue Jiang, Jialing Xie, Han Zhang, Jiayi Jiang, Xiaotian Li, Lei Yao, Suping Zhang, Daohong Zhou, Jianrong Wang
Autophagy protects hematopoietic cells from radiation damage in part by promoting DNA damage repair. However, the molecular mechanisms by which autophagy regulates DNA damage repair remain largely elusive. Here, we report that this radioprotective effect of autophagy depends on STAT3 signaling in murine bone marrow mononuclear cells (BM-MNCs). Specifically, we found that STAT3 activation and nuclear translocation in BM-MNCs were increased by activation of autophagy with an mTOR inhibitor and decreased by knockout of the autophagy gene Atg7...
March 2017: Radiation Research
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