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Epigenetic priming

Sophie Van Linthout, Carsten Tschöpe
PURPOSE OF REVIEW: Myocarditis is an inflammatory disease of the cardiac muscle mainly caused by viral infection. Due to the diverse clinical presentation of myocarditis, accurate diagnosis demands simultaneous histologic, immunohistochemical and molecular biological workup of endomyocardial biopsies (EMBs) as defined by the position statement of the Working Group on Myocardial and Pericardial Diseases of the European Society of Cardiology on myocarditis. RECENT FINDINGS: Endomyocardial biopsy-based analysis of viral transcriptional activity, mRNA expression, epigenetics and region-specific protein expression analysis via imaging mass spectrometry have led to the identification of novel potential diagnostic criteria, markers with prognostic value and therapeutic targets for the treatment of viral myocarditis, opening new avenues for novel therapies, including cell therapies, as well as the use of established treatment options, be it from other indications...
March 9, 2018: Current Opinion in Cardiology
Sergio Lamprecht, Ina Sigal-Batikoff, Shraga Shany, Naim Abu-Freha, Eduard Ling, George J Delinasios, Keren Moyal-Atias, John G Delinasios, Alexander Fich
It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells...
February 27, 2018: Cancers
Anna Altshuler, Mila Verbuk, Swarnabh Bhattacharya, Ifat Abramovich, Roni Haklai, Jacob H Hanna, Yoel Kloog, Eyal Gottlieb, Ruby Shalom-Feuerstein
The transition from naive to primed state of pluripotent stem cells is hallmarked by epithelial-mesenchymal transition, metabolic switch from oxidative phosphorylation to aerobic glycolysis, and changes in the epigenetic landscape. Since these changes are also seen as putative hallmarks of neoplastic cell transformation, we hypothesized that oncogenic pathways may be involved in this process. We report that the activity of RAS is repressed in the naive state of mouse embryonic stem cells (ESCs) and that all three RAS isoforms are significantly activated upon early differentiation induced by LIF withdrawal, embryoid body formation, or transition to the primed state...
February 8, 2018: Stem Cell Reports
Khushboo Agrawal, Viswanath Das, Pankhuri Vyas, Marián Hajdúch
DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development...
February 15, 2018: Pharmacology & Therapeutics
Stefan H Stricker, Magdalena Götz
The pristine formation of complex organs depends on sharp temporal and spatial control of gene expression. Therefore, epigenetic mechanisms have been frequently attributed a central role in controlling cell fate determination. A prime example for this is the first discovered and still most studied epigenetic mark, DNA methylation, and the development of the most complex mammalian organ, the brain. Recently, the field of epigenetics has advanced significantly: new DNA modifications were discovered, epigenomic profiling became widely accessible, and methods for targeted epigenomic manipulation have been developed...
2018: Frontiers in Neuroscience
Yanina Soledad Bogliotti, Jun Wu, Marcela Vilarino, Daiji Okamura, Delia Alba Soto, Cuiqing Zhong, Masahiro Sakurai, Rafael Vilar Sampaio, Keiichiro Suzuki, Juan Carlos Izpisua Belmonte, Pablo Juan Ross
Embryonic stem cells (ESCs) are derived from the inner cell mass of preimplantation blastocysts. From agricultural and biomedical perspectives, the derivation of stable ESCs from domestic ungulates is important for genomic testing and selection, genome engineering, and modeling human diseases. Cattle are one of the most important domestic ungulates that are commonly used for food and bioreactors. To date, however, it remains a challenge to produce stable pluripotent bovine ESC lines. Employing a culture system containing fibroblast growth factor 2 and an inhibitor of the canonical Wnt-signaling pathway, we derived pluripotent bovine ESCs (bESCs) with stable morphology, transcriptome, karyotype, population-doubling time, pluripotency marker gene expression, and epigenetic features...
February 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kaixiang Cao, Clayton K Collings, Marc A Morgan, Stacy A Marshall, Emily J Rendleman, Patrick A Ozark, Edwin R Smith, Ali Shilatifard
Chromatin regulators control cellular differentiation by orchestrating dynamic developmental gene expression programs, and hence, malfunctions in the regulation of chromatin state contribute to both developmental disorders and disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins ASsociated with Set1) protein family that implements histone H3 lysine 4 monomethylation (H3K4me1) at enhancers, is essential for embryonic development and functions as a pancancer tumor suppressor. We define the roles of Mll4/COMPASS and its catalytic activity in the maintenance and exit of ground-state pluripotency in murine embryonic stem cells (ESCs)...
January 2018: Science Advances
Mingchuan Zhao, Yishi Zhang, Jiayu Li, Xuefei Li, Ningning Cheng, Qi Wang, Weijing Cai, Chao Zhao, Yayi He, Jianhua Chang, Caicun Zhou
Drug resistance remains a major challenge in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Bcl-2-like protein 11 (BIM), a B-cell lymphoma 2 family pro-apoptotic protein, is a prime target for specific anti-cancer therapeutics. However, the epigenetic regulation of BIM in non-small cell lung cancer (NSCLC) cell lines and patients with NSCLC in association with EGFR-TKI resistance requires investigation. Methylation-specific PCR (MSP), pyrosequencing, and nested quantitative (q)-MSP were conducted to explore the methylation status of BIM in NSCLC cell lines...
January 2018: Oncology Letters
Manuela Terranova-Barberio, Scott Thomas, Niwa Ali, Nela Pawlowska, Jeenah Park, Gregor Krings, Michael D Rosenblum, Alfredo Budillon, Pamela N Munster
Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy...
December 26, 2017: Oncotarget
Masaki Kinoshita, Austin Smith
Pluripotency denotes the flexible capacity of single cells to give rise to all somatic lineages and typically also the germline. Mouse ES cells and post-implantation epiblast-derived stem cells (EpiSC) are widely used pluripotent cell culture systems. These two in vitro stem cell types have divergent characteristics. They are considered as representative of distinct developmental stages, distinguished by using the terms "naïve" and "primed". A binary description is an over-simplification, however. Here, we discuss an intermediate stage of pluripotency that we term "formative"...
January 23, 2018: Development, Growth & Differentiation
Zimbul Albo, Johannes Gräff
Long-lasting memories form the basis of our identity as individuals and lie central in shaping future behaviours that guide survival. Surprisingly, however, our current knowledge of how such memories are stored in the brain and retrieved, as well as the dynamics of the circuits involved, remains scarce despite seminal technical and experimental breakthroughs in recent years. Traditionally, it has been proposed that, over time, information initially learnt in the hippocampus is stored in distributed cortical networks...
March 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Özgen Deniz, Lorenzo de la Rica, Kevin C L Cheng, Dominik Spensberger, Miguel R Branco
BACKGROUND: Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET-dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos...
January 19, 2018: Genome Biology
Sören Boller, Rui Li, Rudolf Grosschedl
Hematopoiesis is regulated by signals from the microenvironment, transcription factor networks, and changes of the epigenetic landscape. Transcription factors interact with and shape chromatin to allow for lineage- and cell type-specific changes in gene expression. During B lymphopoiesis, epigenetic regulation is observed in multilineage progenitors in which a specific chromatin context is established, at the onset of the B cell differentiation when early B cell factor 1 (EBF1) induces lineage-specific changes in chromatin, during V(D)J recombination and after antigen-driven activation of B cells and terminal differentiation...
January 11, 2018: Trends in Genetics: TIG
Jacob E Schrum, Juliet N Crabtree, Katherine R Dobbs, Michael C Kiritsy, George W Reed, Ricardo T Gazzinelli, Mihai G Netea, James W Kazura, Arlene E Dent, Katherine A Fitzgerald, Douglas T Golenbock
Malarial infection in naive individuals induces a robust innate immune response. In the recently described model of innate immune memory, an initial stimulus primes the innate immune system to either hyperrespond (termed training) or hyporespond (tolerance) to subsequent immune challenge. Previous work in both mice and humans demonstrated that infection with malaria can both serve as a priming stimulus and promote tolerance to subsequent infection. In this study, we demonstrate that initial stimulation with Plasmodium falciparum-infected RBCs or the malaria crystal hemozoin induced human adherent PBMCs to hyperrespond to subsequent ligation of TLR2...
January 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Luigia Pace, Christel Goudot, Elina Zueva, Paul Gueguen, Nina Burgdorf, Joshua J Waterfall, Jean-Pierre Quivy, Geneviève Almouzni, Sebastian Amigorena
After priming, naïve CD8+ T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expression programs. We explored the role of gene silencing by the histone methyltransferase Suv39h1. In murine CD8+ T cells activated after Listeria monocytogenes infection, Suv39h1-dependent trimethylation of histone H3 lysine 9 controls the expression of a set of stem cell-related memory genes...
January 12, 2018: Science
Yanping Wang, Russel J Reiter, Zhulong Chan
Melatonin, a derivative of tryptophan, was detected in plant species in 1995. Melatonin has proven to be a diverse regulator during plant growth, development and stress responses. Recently, great progress has been made toward the detailed functions of melatonin in plant response to abiotic stress. Melatonin priming improved plant tolerance to cold, heat, salt and drought stresses through regulation of genes involved in DREB/CBF, HSF, SOS, and ABA pathways, respectively. As a free radicals scavenger, melatonin also directly detoxifies reactive oxygen species, thus alleviating membrane oxidation...
December 21, 2017: Journal of Experimental Botany
Ralph Stadhouders, Erik Lubberts, Rudi W Hendriks
Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ)...
December 21, 2017: Journal of Autoimmunity
Boris Novakovic, Hendrik G Stunnenberg
Exposure to inflammatory stimuli can remodel immune cells in a way that alters their response to future insults. In a landmark paper in Nature, Elaine Fuchs and colleagues show that memory of inflammation is not restricted to the hematopoietic lineage (Naik et al., 2017).
December 19, 2017: Immunity
Aref Shahini, Debanik Choudhury, Mohammadnabi Asmani, Ruogang Zhao, Pedro Lei, Stelios T Andreadis
Adult skeletal muscle regeneration relies on the activity of satellite cells residing in the skeletal muscle niche. However, systemic and intrinsic factors decrease the myogenic differentiation potential of satellite cells thereby impairing muscle regeneration. Here we present data showing that late passage C2C12 myoblasts exhibited significantly impaired myogenic differentiation potential that was accompanied by impaired expression of myogenic regulatory factors (Myf5, MyoD, Myogenin, and MRF4) and members of myocyte enhancer factor 2 family...
December 2, 2017: Stem Cell Research
Julian R Peat, Sébastien A Smallwood
The epigenetic mark 5-methylcytosine confers heritable regulation of gene expression that can be dynamically modulated during transitions in cell fate. With the development of high-throughput sequencing technologies, it is now possible to obtain comprehensive genome-wide maps of the mammalian DNA methylation landscape, but the application of these techniques to limited material remains challenging. Here, we present an optimized protocol to perform whole-genome bisulfite sequencing on low inputs (100-5000 somatic cells) using a post-bisulfite adapter tagging approach...
2018: Methods in Molecular Biology
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