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De novo DNA Methylation

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https://www.readbyqxmd.com/read/28648661/de-novo-epigenetic-programs-inhibit-pd-1-blockade-mediated-t-cell-rejuvenation
#1
Hazem E Ghoneim, Yiping Fan, Ardiana Moustaki, Hossam A Abdelsamed, Pradyot Dash, Pranay Dogra, Robert Carter, Walid Awad, Geoff Neale, Paul G Thomas, Ben Youngblood
Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28630288/intact-pirna-pathway-prevents-l1-mobilization-in-male-meiosis
#2
Simon J Newkirk, Suman Lee, Fiorella C Grandi, Valeriya Gaysinskaya, James M Rosser, Nicole Vanden Berg, Cathryn A Hogarth, Maria C N Marchetto, Alysson R Muotri, Michael D Griswold, Ping Ye, Alex Bortvin, Fred H Gage, Jef D Boeke, Wenfeng An
The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28624556/a-64-bp-sequence-containing-the-gaaga-motif-is-essential-for-camv-35s-promoter-methylation-in-gentian
#3
Asahi Shimada, Azusa Okumura, Satoshi Yamasaki, Yuji Iwata, Nozomu Koizumi, Masahiro Nishihara, Kei-Ichiro Mishiba
This study investigated sequence specificity and perenniality of DNA methylation in the cauliflower mosaic virus (CaMV) 35S promoter of transgenic gentian (Gentiana triflora×G. scabra) plants. Unlike conventional transgene silencing models, 35S promoter hypermethylation in gentian is species-specific and occurs irrespective of the T-DNA copy number and genomic location. Modified 35S promoters were introduced into gentian, and single-copy transgenic lines were selected for methylation analysis. Modified 35S promoter lacking a core (-90) region [35S(Δcore)] in gentian conferred hypermethylation and high levels of de novo methylation of the CpHpH/CpCpG sites in the 35S enhancer regions (-298 to -241 and -148 to -85)...
June 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28624458/dna-hypomethylation-circuit-of-mouse-rdna-repeats-in-the-germ-cell-lineage
#4
Asuka Furuta, Toshinobu Nakamura
DNA methylation is dynamically reprogrammed at two developmental periods, in primordial germ cells and pre-implantation embryos, via distinct phases of DNA demethylation and de novo methylation. Here we show that ribosomal DNA (rDNA) promoters are hypomethylated in sperm and oocytes; this hypomethyaltion was maintained during pre-implantation development. A DNA methylation analysis of embryonic and extra-embryonic cells on embryonic day 7.5 (E7.5) revealed that the rDNA promoter was slightly methylated in embryonic and extra-embryonic regions...
August 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28614801/dna-methyltransferase-3b-regulates-articular-cartilage-homeostasis-by-altering-metabolism
#5
Jie Shen, Cuicui Wang, Daofeng Li, Taotao Xu, Jason Myers, John M Ashton, Ting Wang, Michael J Zuscik, Audrey McAlinden, Regis J O'Keefe
Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a complex disease affecting the whole joint but is generally characterized by progressive degradation of articular cartilage. Recent genome-wide association screens have implicated distinct DNA methylation signatures in OA patients. We show that the de novo DNA methyltransferase (Dnmt) 3b, but not Dnmt3a, is present in healthy murine and human articular chondrocytes and its expression decreases in OA mouse models and in chondrocytes from human OA patients...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614798/dnmt3a-mediated-inhibition-of-wnt-in-cardiac-progenitor-cells-improves-differentiation-and-remote-remodeling-after-infarction
#6
Aurelia De Pauw, Emilie Andre, Belaid Sekkali, Caroline Bouzin, Hrag Esfahani, Nicolas Barbier, Axelle Loriot, Charles De Smet, Laetitia Vanhoutte, Stéphane Moniotte, Bernhard Gerber, Vittoria di Mauro, Daniele Catalucci, Olivier Feron, Denise Hilfiker-Kleiner, Jean-Luc Balligand
Adult cardiac progenitor cells (CPCs) display a low capacity to differentiate into cardiomyocytes in injured hearts, strongly limiting the regenerative capacity of the mammalian myocardium. To identify new mechanisms regulating CPC differentiation, we used primary and clonally expanded Sca-1+ CPCs from murine adult hearts in homotypic culture or coculture with cardiomyocytes. Expression kinetics analysis during homotypic culture differentiation showed downregulation of Wnt target genes concomitant with increased expression of the Wnt antagonist, Wnt inhibitory factor 1 (Wif1), which is necessary to stimulate CPC differentiation...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28607180/p53-is-essential-for-dna-methylation-homeostasis-in-na%C3%A3-ve-embryonic-stem-cells-and-its-loss-promotes-clonal-heterogeneity
#7
Ayala Tovy, Adam Spiro, Ryan McCarthy, Zohar Shipony, Yael Aylon, Kendra Allton, Elena Ainbinder, Noa Furth, Amos Tanay, Michelle Barton, Moshe Oren
DNA methylation is a key regulator of embryonic stem cell (ESC) biology, dynamically changing between naïve, primed, and differentiated states. The p53 tumor suppressor is a pivotal guardian of genomic stability, but its contributions to epigenetic regulation and stem cell biology are less explored. We report that, in naïve mouse ESCs (mESCs), p53 restricts the expression of the de novo DNA methyltransferases Dnmt3a and Dnmt3b while up-regulating Tet1 and Tet2, which promote DNA demethylation. The DNA methylation imbalance in p53-deficient (p53(-/-)) mESCs is the result of augmented overall DNA methylation as well as increased methylation landscape heterogeneity...
May 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28596259/morphologic-and-molecular-characteristics-of-de-novo-aml-with-jak2-v617f-mutation
#8
Juliana E Hidalgo-López, Rashmi Kanagal-Shamanna, L Jeffrey Medeiros, Zeev Estrov, C Cameron Yin, Srdan Verstovsek, Sergej Konoplev, Jeffrey L Jorgensen, Mohammad M Mohammad, Roberto N Miranda, Chong Zhao, John Lee, Zhuang Zuo, Carlos E Bueso-Ramos
Background:JAK2 V617F mutation (mut) in acute myeloid leukemia (AML) is rare. We describe the clinicopathologic findings of a single-institution series of 11 de novo AML cases with JAK2 V617. Methods: We identified cases of de novo AML with JAK2 V617F over a 10-year period. We reviewed diagnostic peripheral blood and bone marrow (BM) morphologic, cytogenetic, and molecular studies, including next-generation sequencing. The control group consisted of 12 patients with JAK2 wild-type (wt) AML matched for age, sex, and diagnosis...
June 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28581499/high-quality-de-novo-assembly-of-the-apple-genome-and-methylome-dynamics-of-early-fruit-development
#9
Nicolas Daccord, Jean-Marc Celton, Gareth Linsmith, Claude Becker, Nathalie Choisne, Elio Schijlen, Henri van de Geest, Luca Bianco, Diego Micheletti, Riccardo Velasco, Erica Adele Di Pierro, Jérôme Gouzy, D Jasper G Rees, Philippe Guérif, Hélène Muranty, Charles-Eric Durel, François Laurens, Yves Lespinasse, Sylvain Gaillard, Sébastien Aubourg, Hadi Quesneville, Detlef Weigel, Eric van de Weg, Michela Troggio, Etienne Bucher
Using the latest sequencing and optical mapping technologies, we have produced a high-quality de novo assembly of the apple (Malus domestica Borkh.) genome. Repeat sequences, which represented over half of the assembly, provided an unprecedented opportunity to investigate the uncharacterized regions of a tree genome; we identified a new hyper-repetitive retrotransposon sequence that was over-represented in heterochromatic regions and estimated that a major burst of different transposable elements (TEs) occurred 21 million years ago...
July 2017: Nature Genetics
https://www.readbyqxmd.com/read/28575854/genomic-alterations-in-mucins-across-cancers
#10
Ryan J King, Fang Yu, Pankaj K Singh
The significance of mucins in cancers has led to the development of novel biomarkers and therapeutic agents against cancers. Despite significant advances in the understanding of mucins, systemic investigations into the role of mucins in cancer biology focusing particularly on the histological subtypes and stages, along with other variables, are yet to be carried out to discover potential novel functions and cancer-specific roles. Here, we investigated 11 mucin expressing cancers for DNA mutations, mRNA expression, copy number, methylation, and the impacts these genomic features may have on patient survival by utilizing The Cancer Genome Atlas dataset...
May 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28541567/dna-methylation-and-small-interference-rnas-participate-in-the-regulation-of-mads-box-genes-involved-in-dormancy-in-sweet-cherry-prunus-avium-l
#11
Karin Rothkegel, Evelyn Sánchez, Christian Montes, Macarena Greve, Sebastián Tapia, Soraya Bravo, Humberto Prieto, Andréa Miyasaka Almeida
Epigenetic modifications can yield information about connections between genotype, phenotype variation and environmental conditions. Bud dormancy release in temperate perennial fruit trees depends on internal and environmental signals such as cold accumulation and photoperiod. Previous investigations have noted the participation of epigenetic mechanisms in the control of this physiological process. We examined whether epigenetic modifications were modulated in MADS-box genes, potential candidates for the regulation of bud dormancy and flowering in sweet cherry (Prunus avium L...
May 24, 2017: Tree Physiology
https://www.readbyqxmd.com/read/28513272/neuronal-dna-methyltransferases-epigenetic-mediators-between-synaptic-activity-and-gene-expression
#12
Gonca Bayraktar, Michael R Kreutz
DNMT3A and 3B are the main de novo DNA methyltransferases (DNMTs) in the brain that introduce new methylation marks to non-methylated DNA in postmitotic neurons. DNA methylation is a key epigenetic mark that is known to regulate important cellular processes in neuronal development and brain plasticity. Accumulating evidence disclosed rapid and dynamic changes in DNA methylation of plasticity-relevant genes that are important for learning and memory formation. To understand how DNMTs contribute to brain function and how they are regulated by neuronal activity is a prerequisite for a deeper appreciation of activity-dependent gene expression in health and disease...
May 1, 2017: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
https://www.readbyqxmd.com/read/28510781/5-azacytidine-mediated-reactivation-of-silenced-transgenes-in-potato-solanum-tuberosum-at-the-whole-plant-level
#13
Dimitrij Tyč, Eva Nocarová, Lenka Sikorová, Lukáš Fischer
Transient 5-azacytidine treatment of leaf explants from potato plants with transcriptionally silenced transgenes allows de novo regeneration of plants with restored transgene expression at the whole plant level. Transgenes introduced into plant genomes frequently become silenced either at the transcriptional or the posttranscriptional level. Transcriptional silencing is usually associated with DNA methylation in the promoter region. Treatments with inhibitors of maintenance DNA methylation were previously shown to allow reactivation of transcriptionally silenced transgenes in single cells or tissues, but not at the whole plant level...
August 2017: Plant Cell Reports
https://www.readbyqxmd.com/read/28507606/transcription-and-chromatin-determinants-of-de-novo-dna-methylation-timing-in-oocytes
#14
Lenka Gahurova, Shin-Ichi Tomizawa, Sébastien A Smallwood, Kathleen R Stewart-Morgan, Heba Saadeh, Jeesun Kim, Simon R Andrews, Taiping Chen, Gavin Kelsey
BACKGROUND: Gametogenesis in mammals entails profound re-patterning of the epigenome. In the female germline, DNA methylation is acquired late in oogenesis from an essentially unmethylated baseline and is established largely as a consequence of transcription events. Molecular and functional studies have shown that imprinted genes become methylated at different times during oocyte growth; however, little is known about the kinetics of methylation gain genome wide and the reasons for asynchrony in methylation at imprinted loci...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28503201/dna-methylation-and-dna-methyltransferases
#15
REVIEW
John R Edwards, Olya Yarychkivska, Mathieu Boulard, Timothy H Bestor
The prevailing views as to the form, function, and regulation of genomic methylation patterns have their origin many years in the past, at a time when the structure of the mammalian genome was only dimly perceived, when the number of protein-encoding mammalian genes was believed to be at least five times greater than the actual number, and when it was not understood that only ~10% of the genome is under selective pressure and likely to have biological function. We use more recent findings from genome biology and whole-genome methylation profiling to provide a reappraisal of the shape of genomic methylation patterns and the nature of the changes that they undergo during gametogenesis and early development...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28498935/the-association-of-changes-in-dna-methylation-with-temperature-dependent-sex-determination-in-cucumber
#16
Yun-Song Lai, Xiaohui Zhang, Wei Zhang, Di Shen, Haiping Wang, Yudong Xia, Yang Qiu, Jiangping Song, Chenchen Wang, Xixiang Li
Cucumber (Cucumis sativus L.) is characterized by its diverse and flexible sexual types. Here, we evaluated the effect of low temperature (LT) exposure on cucumber femaleness under short-day conditions. Shoot apices were subjected to whole-genome bisulfate sequencing (WGBS), mRNA-seq, and sRNA-seq. The results showed that temperature had a substantial and global impact on transposable element (TE)-related small RNA-directed DNA methylation (RdDM) mechanisms, resulting in large amounts of CHH-type cytosine demethylation...
May 12, 2017: Journal of Experimental Botany
https://www.readbyqxmd.com/read/28491150/dynamic-silencing-of-somatic-l1-retrotransposon-insertions-reflects-the-developmental-and-cellular-contexts-of-their-genomic-integration
#17
Manoj Kannan, Jingfeng Li, Sarah E Fritz, Kathryn E Husarek, Jonathan C Sanford, Teresa L Sullivan, Pawan Kumar Tiwary, Wenfeng An, Jef D Boeke, David E Symer
BACKGROUND: The ongoing mobilization of mammalian transposable elements (TEs) contributes to natural genetic variation. To survey the epigenetic control and expression of reporter genes inserted by L1 retrotransposition in diverse cellular and genomic contexts, we engineered highly sensitive, real-time L1 retrotransposon reporter constructs. RESULTS: Here we describe different patterns of expression and epigenetic controls of newly inserted sequences retrotransposed by L1 in various somatic cells and tissues including cultured human cancer cells, mouse embryonic stem cells, and tissues of pseudofounder transgenic mice and their progeny...
2017: Mobile DNA
https://www.readbyqxmd.com/read/28486105/chd4-has-oncogenic-functions-in-initiating-and-maintaining-epigenetic-suppression-of-multiple-tumor-suppressor-genes
#18
Limin Xia, Wenjie Huang, Marina Bellani, Michael M Seidman, Kaichun Wu, Daiming Fan, Yongzhan Nie, Yi Cai, Yang W Zhang, Li-Rong Yu, Huili Li, Cynthia A Zahnow, Wenbing Xie, Ray-Whay Chiu Yen, Feyruz V Rassool, Stephen B Baylin
An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks...
May 8, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28473583/integration-of-cpg-free-dna-induces-de-novo-methylation-of-cpg-islands-in-pluripotent-stem-cells
#19
Yuta Takahashi, Jun Wu, Keiichiro Suzuki, Paloma Martinez-Redondo, Mo Li, Hsin-Kai Liao, Min-Zu Wu, Reyna Hernández-Benítez, Tomoaki Hishida, Maxim Nikolaievich Shokhirev, Concepcion Rodriguez Esteban, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte
CpG islands (CGIs) are primarily promoter-associated genomic regions and are mostly unmethylated within highly methylated mammalian genomes. The mechanisms by which CGIs are protected from de novo methylation remain elusive. Here we show that insertion of CpG-free DNA into targeted CGIs induces de novo methylation of the entire CGI in human pluripotent stem cells (PSCs). The methylation status is stably maintained even after CpG-free DNA removal, extensive passaging, and differentiation. By targeting the DNA mismatch repair gene MLH1 CGI, we could generate a PSC model of a cancer-related epimutation...
May 5, 2017: Science
https://www.readbyqxmd.com/read/28448738/site-specific-recruitment-of-epigenetic-factors-with-a-modular-crispr-cas-system
#20
Tobias Anton, Sebastian Bultmann
Dissecting the complex network of epigenetic modifications requires tools that combine precise recognition of DNA sequences with the capability to modify epigenetic marks. The CRISPR/Cas system has been proven to be a valuable addition to existing methodologies that fulfill these tasks. So far, sequence-specific editing of epigenetic modifications such as DNA methylation and histone posttranslational modifications relied on direct fusions of enzymatically inactivated Cas9 (dCas9) with epigenetic effectors. Here, we report a novel, modular system that facilitates the recruitment of any GFP-tagged protein to desired genomic loci...
May 4, 2017: Nucleus
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