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Epigenetic priming

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https://www.readbyqxmd.com/read/28796629/hepatic-lipid-accumulation-and-nrf2-expression-following-perinatal-and-peripubertal-exposure-to-bisphenol-a-in-a-mouse-model-of-nonalcoholic-liver-disease
#1
Prajakta C Shimpi, Vijay R More, Maneesha Paranjpe, Ajay C Donepudi, Jaclyn M Goodrich, Dana C Dolinoy, Beverly Rubin, Angela L Slitt
BACKGROUND: Exposure to chemicals during critical windows of development may re-program liver for increased risk of nonalcoholic fatty liver disease (NAFLD). Bisphenol A (BPA), a plastics component, has been described to impart adverse effects during gestational and lactational exposure. Our work has pointed to nuclear factor E2-related factor 2 (Nrf2) being a modulator of hepatic lipid accumulation in models of NAFLD. OBJECTIVES: To determine if chemical exposure can prime liver for steatosis via modulation of NRF2 and epigenetic mechanisms...
August 4, 2017: Environmental Health Perspectives
https://www.readbyqxmd.com/read/28765214/epigenetic-resetting-of-human-pluripotency
#2
Ge Guo, Ferdinand von Meyenn, Maria Rostovskaya, James Clarke, Sabine Dietmann, Duncan Baker, Anna Sahakyan, Samuel Myers, Paul Bertone, Wolf Reik, Kathrin Plath, Austin Smith
Much attention has focussed on the conversion of human pluripotent stem cells (PSCs) to a more naïve developmental status. Here we provide a method for resetting via transient histone deacetylase inhibition. The protocol is effective across multiple PSC lines and can proceed without karyotype change. Reset cells can be expanded without feeders with a doubling time of around 24 h. WNT inhibition stabilises the resetting process. The transcriptome of reset cells diverges markedly from that of primed PSCs and shares features with human inner cell mass (ICM)...
August 1, 2017: Development
https://www.readbyqxmd.com/read/28759843/trim28-epigenetic-corepressor-is-indispensable-for-stable-induced-pluripotent-stem-cell-formation
#3
Marta Klimczak, Patrycja Czerwińska, Sylwia Mazurek, Barbara Sozańska, Przemysław Biecek, Andrzej Mackiewicz, Maciej Wiznerowicz
Cellular reprogramming proceeds in a stepwise pathway initiated by binding and transcription of pluripotency factors followed by genome-wide epigenetic changes. Priming events, such as erasure of DNA methylation and chromatin remodeling determines the success of pluripotency acquisition later. Therefore, growing efforts are made to understand epigenetic regulatory network that makes reprogramming possible and efficient. Here, we analyze the role of transcriptional corepressor TRIM28, involved in heterochromatin formation, during the process of reprogramming of mouse somatic cells into induced pluripotent stem cells (iPS cells)...
July 15, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28752860/enhancing-the-cytotoxicity-of-chemoradiation-with-radiation-guided-delivery-of-anti-mgmt-morpholino-oligonucleotides-in-non-methylated-solid-tumors
#4
P Ambady, Y J Wu, J M Walker, C Kersch, M A Pagel, R L Woltjer, R Fu, L L Muldoon, E A Neuwelt
The DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences...
July 28, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28729399/decitabine-priming-enhances-mucin-1-inhibition-mediated-disruption-of-redox-homeostasis-in-cutaneous-t-cell-lymphoma
#5
Salvia Jain, Abigail Washington, Rebecca Karp Leaf, Parul Bhargava, Rachael A Clark, Thomas S Kupper, Dina Stroopinsky, Athalia Pyzer, Leandra Cole, Myrna Nahas, Arie Apel, Jacalyn Rosenblatt, Jon Arnason, Donald Kufe, David Avigan
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the MUC1-C oncoprotein plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28701277/the-epigenetic-architecture-at-gene-promoters-determines-cell-type-specific-lps-tolerance
#6
Kerstin Klein, Mojca Frank-Bertoncelj, Emmanuel Karouzakis, Renate E Gay, Christoph Kolling, Adrian Ciurea, Nagihan Bostanci, Georgios N Belibasakis, Lih-Ling Lin, Oliver Distler, Steffen Gay, Caroline Ospelt
Synovial fibroblasts (SF) drive inflammation and joint destruction in chronic arthritis. Here we show that SF possess a distinct type of LPS tolerance compared to macrophages and other types of fibroblasts. In SF and dermal fibroblasts, genes that were non-tolerizable after repeated LPS stimulation included pro-inflammatory cytokines, chemokines and matrix metalloproteinases, whereas anti-viral genes were tolerizable. In macrophages, all measured genes were tolerizable, whereas in gingival and foreskin fibroblasts these genes were non-tolerizable...
July 9, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28677769/valproic-acid-enforces-the-priming-effect-of-sphingosine-1-phosphate-on-human-mesenchymal-stem-cells
#7
Jisun Lim, Seungun Lee, Hyein Ju, Yonghwan Kim, Jinbeom Heo, Hye-Yeon Lee, Kyung-Chul Choi, Jaekyoung Son, Yeon-Mok Oh, In-Gyu Kim, Dong-Myung Shin
Engraftment and homing of mesenchymal stem cells (MSCs) are modulated by priming factors including the bioactive lipid sphingosine-1-phosphate (S1P), by stimulating CXCR4 receptor signaling cascades. However, limited in vivo efficacy and the remaining priming molecules prior to administration of MSCs can provoke concerns regarding the efficiency and safety of MSC priming. Here, we showed that valproic acid (VPA), a histone deacetylase inhibitor, enforced the priming effect of S1P at a low dosage for human umbilical cord-derived MSCs (UC-MSCs)...
July 3, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28670929/exploiting-the-pro-apoptotic-function-of-noxa-as-a-therapeutic-modality-in-cancer
#8
REVIEW
Jeroen E Guikema, Martine Amiot, Eric Eldering
Direct targeting of Bcl-2 members for therapeutic purposes in cancer has become a clinical reality with the FDA approval of ABT-199/Venetoclax. Other highly specific BH3-mimetics are in pre-clinical development. Understanding the functional interactions among the Bcl-2 family is of prime importance to fully exploit their potential. NOXA is considered a rather weak BH3-only member but it has unexplored potential in various settings, which are of relevance in cancer. NOXA is best known as a selective inhibitor of MCL1, itself overexpressed in many cancers, and this protein pair forms an important rheostat in many forms of cell stress...
August 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28661724/sirt1-and-sirt6-signaling-pathways-in-cardiovascular-disease-protection
#9
Nunzia D'Onofrio, Luigi Servillo, Maria Luisa Balestrieri
SIGNIFICANCE: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD(+))-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD...
June 29, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28650429/acetate-mediated-novel-survival-strategy-against-drought-in-plants
#10
Jong-Myong Kim, Taiko Kim To, Akihiro Matsui, Keitaro Tanoi, Natsuko I Kobayashi, Fumio Matsuda, Yoshiki Habu, Daisuke Ogawa, Takuya Sakamoto, Sachihiro Matsunaga, Khurram Bashir, Sultana Rasheed, Marina Ando, Hiroko Takeda, Kanako Kawaura, Miyako Kusano, Atsushi Fukushima, Takaho A Endo, Takashi Kuromori, Junko Ishida, Taeko Morosawa, Maho Tanaka, Chieko Torii, Yumiko Takebayashi, Hitoshi Sakakibara, Yasunari Ogihara, Kazuki Saito, Kazuo Shinozaki, Alessandra Devoto, Motoaki Seki
Water deficit caused by global climate changes seriously endangers the survival of organisms and crop productivity, and increases environmental deterioration(1,2). Plants' resistance to drought involves global reprogramming of transcription, cellular metabolism, hormone signalling and chromatin modification(3-8). However, how these regulatory responses are coordinated via the various pathways, and the underlying mechanisms, are largely unknown. Herein, we report an essential drought-responsive network in which plants trigger a dynamic metabolic flux conversion from glycolysis into acetate synthesis to stimulate the jasmonate (JA) signalling pathway to confer drought tolerance...
June 26, 2017: Nature Plants
https://www.readbyqxmd.com/read/28628715/overcoming-the-resistance-of-pancreatic-cancer-to-immune-checkpoint-inhibitors
#11
REVIEW
Richard A Skelton, Ammar Javed, Lei Zheng, Jin He
Immunotherapy has become a new modality of cancer treatment, but has had a limited success in treating PDAC. A combination approach to immunotherapy, using both immune checkpoint inhibitors and immune activating agonists, is needed, as PDAC does not respond to single-agent checkpoint inhibitors. Studies have also supported using vaccine-based therapies to prime the tumor microenvironment of PDAC with effector T-cells. Other therapeutic strategies including epigenetic agents, stroma modulators, radiotherapy, and T-cell transfer therapies may also prime the tumor microenvironment to overcome resistance to immune checkpoint inhibitors...
July 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28619824/setd1b-encoding-a-histone-3-lysine-4-methyltransferase-is-a-maternal-effect-gene-required-for-the-oogenic-gene-expression-program
#12
David Brici, Qinyu Zhang, Susanne Reinhardt, Andreas Dahl, Hella Hartmann, Kerstin Schmidt, Neha Goveas, Jiahao Huang, Lenka Gahurova, Gavin Kelsey, Konstantinos Anastassiadis, A Francis Stewart, Andrea Kranz
Germ cell development involves major reprogramming of the epigenome to prime the zygote for totipotency. Histone 3 lysine 4 (H3K4) methylations are universal epigenetic marks mediated in mammals by six H3K4 methyltransferases related to fly Trithorax, including two yeast Set1 orthologs: Setd1a and Setd1b. Whereas Setd1a plays no role in oogenesis, we report that Setd1b deficiency causes female sterility in mice. Oocyte-specific Gdf9-iCre conditional knockout (Setd1b(Gdf9) cKO) ovaries develop through all stages; however, follicular loss accumulated with age and unfertilized metaphase II (MII) oocytes exhibited irregularities of the zona pellucida and meiotic spindle...
July 15, 2017: Development
https://www.readbyqxmd.com/read/28611305/kdm4a-as-a-prognostic-marker-of-oral-squamous-cell-carcinoma-evidence-from-tissue-microarray-studies-in-a-multicenter-cohort
#13
Xin Jin, Hao Xu, Xingyu Wu, Taiwen Li, Jing Li, Yu Zhou, Hongxia Dan, Lu Jiang, Xin Zeng, Ping Ji, Qianming Chen
PURPOSE: Previous studies have identified histone demethylase KDM4A to be a key epigenetic priming factor for the invasive squamous cell carcinoma growth and metastasis. The purpose of this study was to examine KDM4A as an independent prognostic marker in oral squamous cell carcinoma, using multicenter tissue microarrays. RESULTS: The expression of KDM4A was significantly correlated with lymph node metastasis and TNM stage. KDM4A overexpression was associated with poor overall survival, and it was found to be a statistically significant independent predictor of all-cause mortality...
May 30, 2017: Oncotarget
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
#14
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/28570543/a-simple-method-to-identify-kinases-that-regulate-embryonic-stem-cell-pluripotency-by-high-throughput-inhibitor-screening
#15
Charles A C Williams, Nathanael S Gray, Greg M Findlay
Embryonic stem cells (ESCs) can self-renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed "naïve" and "primed" pluripotency. The mechanisms that control naïve-primed transition are poorly understood. In particular, we remain poorly informed about protein kinases that specify naïve and primed pluripotent states, despite increasing availability of high-quality tool compounds to probe kinase function. Here, we describe a scalable platform to perform targeted small molecule screens for kinase regulators of the naïve-primed pluripotent transition in mouse ESCs...
May 12, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28561043/hsps-drive-dichotomous-t-cell-immune-responses-via-dna-methylome-remodelling-in-antigen-presenting-cells
#16
Lauren B Kinner-Bibeau, Abigail L Sedlacek, Michelle N Messmer, Simon C Watkins, Robert J Binder
Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91. Global DNMT-dependent epigenetic modifications lead to changes in protein expression within these antigen-presenting cells...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28555084/mitoxantrone-etoposide-and-cytarabine-following-epigenetic-priming-with-decitabine-in-adults-with-relapsed-refractory-acute-myeloid-leukemia-or-other-high-grade-myeloid-neoplasms-a-phase-1-2-study
#17
A B Halpern, M Othus, E M Huebner, S A Buckley, E L Pogosova-Agadjanyan, K F Orlowski, B L Scott, P S Becker, P C Hendrie, T L Chen, M-E M Percival, E H Estey, D L Stirewalt, R B Walter
DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide and cytarabine following 'priming' with 5-10 days of decitabine (dec/MEC) in 52 adults (median age 55 (range: 19-72) years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6-12 patients, all dose levels were well tolerated. As response rates appeared similar with 7 and 10 days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D)...
May 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28545880/stepwise-preconditioning-enhances-mesenchymal-stem-cell-based-cartilage-regeneration-through-epigenetic-modification
#18
S Lin, W Y W Lee, L Xu, Y Wang, Y Chen, K K W Ho, L Qin, X Jiang, L Cui, G Li
OBJECTIVE: This study is to investigate the functions and underlying mechanisms of mesenchymal stem cells (MSCs) underwent stepwise preconditioning in chondrogenic medium before expansion, then further explore their therapeutic effects in a surgically induced osteoarthritis (OA) model. METHODS: MSCs isolated from the adult rats expressing Green Fluorescence Protein (GFP) were incubated in basal medium or primed in chondrogenic medium before expansion. The multipotency including cell proliferation, differentiation, and survivability was compared between chondrogenic manipulated MSCs (M-MSCs) and untreated MSCs...
May 22, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28537488/capturing-human-na%C3%A3-ve-pluripotency-in-the-embryo-and-in-the-dish
#19
Ludovic Zimmerlin, Tea Soon Park, Elias T Zambidis
Although human embryonic stem cells (hESCs) were first derived almost 20 years ago, it was only recently acknowledged that they share closer molecular and functional identity to postimplantation lineage-primed murine epiblast stem cells than to naïve preimplantation inner cell mass-derived mouse ESCs (mESCs). A myriad of transcriptional, epigenetic, biochemical, and metabolic attributes have now been described that distinguish naïve and primed pluripotent states in both rodents and humans. Conventional hESCs and human induced pluripotent stem cells (hiPSCs) appear to lack many of the defining hallmarks of naïve mESCs...
August 15, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28536458/epigenetic-priming-restores-the-hla-class-i-antigen-processing-machinery-expression-in-merkel-cell-carcinoma
#20
Cathrin Ritter, Kaiji Fan, Annette Paschen, Sine Reker Hardrup, Soldano Ferrone, Paul Nghiem, Selma Ugurel, David Schrama, Jürgen C Becker
Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host's immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines. This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2...
May 23, 2017: Scientific Reports
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