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https://www.readbyqxmd.com/read/28456008/donor-dependent-and-other-nondefined-factors-have-greater-influence-on-the-hepatic-phenotype-than-the-starting-cell-type-in-induced-pluripotent-stem-cell-derived-hepatocyte-like-cells
#1
James A Heslop, Richard Kia, Christopher S Pridgeon, Rowena L Sison-Young, Triantafillos Liloglou, Mohamed Elmasry, Stephen W Fenwick, John S Mills, Neil R Kitteringham, Chris E Goldring, Bong K Park
Drug-induced liver injury is the greatest cause of post-marketing drug withdrawal; therefore, substantial resources are directed toward triaging potentially dangerous new compounds at all stages of drug development. One of the major factors preventing effective screening of new compounds is the lack of a predictive in vitro model of hepatotoxicity. Primary human hepatocytes offer a metabolically relevant model for which the molecular initiating events of hepatotoxicity can be examined; however, these cells vary greatly between donors and dedifferentiate rapidly in culture...
May 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28451358/synthetically-controlling-dendrimer-flexibility-improves-delivery-of-large-plasmid-dna
#2
Jessica A Kretzmann, Diwei Ho, Cameron W Evans, Janice H C Plani-Lam, Benjamin Garcia-Bloj, A Elaaf Mohamed, Megan L O'Mara, Ethan Ford, Dennis E K Tan, Ryan Lister, Pilar Blancafort, Marck Norret, K Swaminathan Iyer
Tools for editing the genome and epigenome have revolutionised the field of molecular biology and represent a new frontier in targeted therapeutic intervention. Although efficiencies and specificities of genome editing technologies have improved with the development of TALEs and CRISPR platforms, intracellular delivery of these larger constructs still remains a challenge using existing delivery agents. Viral vectors, including lentiviruses and adeno-associated viruses, as well as some non-viral strategies, such as cationic polymers and liposomes, are limited by packaging capacity, poor delivery, toxicity, and immunogenicity...
April 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28450214/omics-analysis-of-human-bone-to-identify-genes-and-molecular-networks-regulating-skeletal-remodeling-in-health-and-disease
#3
REVIEW
Sjur Reppe, Harish K Datta, Kaare M Gautvik
The skeleton is a metabolically active organ throughout life where specific bone cell activity and paracrine/endocrine factors regulate its morphogenesis and remodeling. In recent years, an increasing number of reports have used multi-omics technologies to characterize subsets of bone biological molecular networks. The skeleton is affected by primary and secondary disease, lifestyle and many drugs. Therefore, to obtain relevant and reliable data from well characterized patient and control cohorts are vital...
April 24, 2017: Bone
https://www.readbyqxmd.com/read/28448742/choreography-of-parental-histones-in-damaged-chromatin
#4
Juliette Dabin, Sophie E Polo
In the cell nucleus, DNA repair machineries operate on a chromatin substrate, whose integrity is key for preserving cell functions and identity. Yet, it is still unclear how the epigenetic information conveyed by chromatin is maintained during the DNA repair process. We recently characterized the dynamics of parental histones coupled to UV-C damage repair in human cells, providing insights into how the pre-damage chromatin state may be restored. Here, we summarize our main findings and discuss them in the context of epigenome maintenance following DNA damage...
February 23, 2017: Nucleus
https://www.readbyqxmd.com/read/28445736/systematic-epigenomic-analysis-reveals-chromatin-states-associated-with-melanoma-progression
#5
Petko Fiziev, Kadir C Akdemir, John P Miller, Emily Z Keung, Neha S Samant, Sneha Sharma, Christopher A Natale, Christopher J Terranova, Mayinuer Maitituoheti, Samirkumar B Amin, Emmanuel Martinez-Ledesma, Mayura Dhamdhere, Jacob B Axelrad, Amiksha Shah, Christine S Cheng, Harshad Mahadeshwar, Sahil Seth, Michelle C Barton, Alexei Protopopov, Kenneth Y Tsai, Michael A Davies, Benjamin A Garcia, Ido Amit, Lynda Chin, Jason Ernst, Kunal Rai
The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways...
April 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28444219/dna-methylation-of-a-novel-pak4-locus-influences-ototoxicity-susceptibility-following-cisplatin-and-radiation-therapy-for-pediatric-embryonal-tumors
#6
Austin L Brown, Kayla L Foster, Philip J Lupo, Erin C Peckham-Gregory, Jeffrey C Murray, M Fatih Okcu, Ching C Lau, Surya P Rednam, Murali Chintagumpala, Michael E Scheurer
Background: Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, the objective of this study was to conduct an epigenome-wide association study to identify differentially methylated CpG sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors. Methods: Samples were collected for a discovery (n=62) and a replication cohort (n=18) of medulloblastoma and primitive neuroectodermal tumor patients...
April 24, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28444216/dietary-metabolites-derived-from-gut-microbiota-critical-modulators-of-epigenetic-changes-in-mammals
#7
Mohd Iqbal Bhat, Rajeev Kapila
The mammalian gastrointestinal tract harbors trillions of commensal microorganisms, collectively known as the microbiota. The microbiota is a critical source of environmental stimuli and, thus, has a tremendous impact on the health of the host. The microbes within the microbiota regulate homeostasis within the gut, and any alteration in their composition can lead to disorders that include inflammatory bowel disease, allergy, autoimmune disease, diabetes, mental disorders, and cancer. Hence, restoration of the gut flora following changes or imbalance is imperative for the host...
April 22, 2017: Nutrition Reviews
https://www.readbyqxmd.com/read/28444195/dna-methylome-analysis-reveals-distinct-epigenetic-patterns-of-ascending-aortic-dissection-and-bicuspid-aortic-valve
#8
Sun Pan, Hao Lai, Yiru Shen, Charles Breeze, Stephan Beck, Tao Hong, Chunsheng Wang, Andrew E Teschendorff
Epigenetics may mediate the effects of environmental risk factors on disease, including heart disease. Thus, measuring the DNA methylome offers the opportunity to identify novel disease biomarkers and novel insights into disease mechanisms. The DNA methylation landscape of ascending aortic dissection (AD) and bicuspid aortic valve (BAV) with aortic aneurysmal dilatation remain uncharacterized. The present study aimed to explore the genome-wide DNA methylation landscape underpinning these two diseases. Methods and results: We used Illumina 450k DNA methylation beadarrays to analyze 21 ascending aorta samples, including 10 cases with AD, 5 with BAV and 6 healthy controls...
April 19, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28443631/a-peripheral-epigenetic-signature-of-immune-system-genes-is-linked-to-neocortical-thickness-and-memory
#9
Virginie Freytag, Tania Carrillo-Roa, Annette Milnik, Philipp G Sämann, Vanja Vukojevic, David Coynel, Philippe Demougin, Tobias Egli, Leo Gschwind, Frank Jessen, Eva Loos, Wolfgang Maier, Steffi G Riedel-Heller, Martin Scherer, Christian Vogler, Michael Wagner, Elisabeth B Binder, Dominique J-F de Quervain, Andreas Papassotiropoulos
Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10(-8)) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls...
April 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28443096/the-microbiota-and-epigenetic-regulation-of-t-helper-17-regulatory-t-cells-in-search-of-a-balanced-immune-system
#10
REVIEW
Annie Luo, Steven T Leach, Romain Barres, Luke B Hesson, Michael C Grimm, David Simar
Immune cells not only affect tissue homeostasis at the site of inflammation but also exert systemic effects contributing to multiple chronic conditions. Recent evidence clearly supports an altered T helper 17/regulatory T cell (Th17/Treg) balance leading to the development and progression of inflammatory diseases that not only affect the gastrointestinal tract but also have whole-body manifestations, including insulin resistance. Epigenetic mechanisms are amenable to both environmental and circulating factors and contribute to determining the T cell landscape...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28442587/combined-aurka-and-h3k9-methyltransferase-targeting-inhibits-cell-growth-by-inducing-mitotic-catastrophe
#11
Angela Mathison, Ann Salmonson, Mckenna Missfeldt, Jennifer Bintz, Monique Williams, Sarah Kossak, Asha Nair, Thiago M de Assuncao, Trace A Christensen, Navtej S Buttar, Juan L Iovanna, Robert Huebert, Gwen Lomberk
The current integrative pathobiological hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation-based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in 3D spheroids and organoids...
April 25, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28442560/obesity-and-menopause-modify-the-epigenomic-profile-of-breast-cancer
#12
Ana B Crujeiras, Angel Díaz-Lagares, Olafur A Stefansson, Manuel Macias, Juan Sandoval, Juan Cueva, Rafael López-López, Sebastian Moran, Jon G Jonasson, Laufey Tryggvadottir, Elinborg Olafsdottir, Francisco J Tinahones, Marcos C Carreira, Felipe F Casanueva, Manel Esteller
Obesity is a high risk factor for breast cancer. This relationship could be marked by a specific methylome. The current work was aimed to explore the impact of obesity and menopausal status on variation in breast cancer methylomes. Data from Infinium 450K array-based methylomes of 64 breast tumor were coupled with information on BMI and menopausal status. Additionally, DNA methylation results were validated in 18 non-tumor and 81 tumor breast samples. Breast tumors arising in either pre- or postmenopausal women stratified by BMI or menopausal status alone were not associated with a specific DNA methylation pattern...
April 25, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28441426/identification-of-genes-associated-with-dissociation-of-cognitive-performance-and-neuropathological-burden-multistep-analysis-of-genetic-epigenetic-and-transcriptional-data
#13
Charles C White, Hyun-Sik Yang, Lei Yu, Lori B Chibnik, Robert J Dawe, Jingyun Yang, Hans-Ulrich Klein, Daniel Felsky, Alfredo Ramos-Miguel, Konstantinos Arfanakis, William G Honer, Reisa A Sperling, Julie A Schneider, David A Bennett, Philip L De Jager
INTRODUCTION: The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. METHODS AND FINDINGS: "Residual cognition" was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487)...
April 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28439570/epigenomics-of-human-cd8-t-cell-differentiation-and-aging
#14
David M Moskowitz, David W Zhang, Bin Hu, Sabine Le Saux, Rolando E Yanes, Zhongde Ye, Jason D Buenrostro, Cornelia M Weyand, William J Greenleaf, Jörg J Goronzy
The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naïve cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we inferred the transcription factor binding activities correlated with naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles implicated for BATF, ETS1, Eomes, and Sp1...
February 2017: Science Immunology
https://www.readbyqxmd.com/read/28439531/genome-and-cd4-t-cell-methylome-wide-association-study-of-circulating-trimethylamine-n-oxide-in-the-genetics-of-lipid-lowering-drugs-and-diet-network-goldn
#15
Stella Aslibekyan, Marguerite R Irvin, Bertha A Hidalgo, Rodney T Perry, Elias J Jeyarajah, Erwin Garcia, Irina Shalaurova, Paul N Hopkins, Michael A Province, Hemant K Tiwari, Jose M Ordovas, Devin M Absher, Donna K Arnett
BACKGROUND: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. METHODS AND RESULTS: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans...
June 2017: Journal of Nutrition & Intermediary Metabolism
https://www.readbyqxmd.com/read/28432132/do-memory-cd4-t-cells-keep-their-cell-type-programming-plasticity-versus-fate-commitment-epigenome-a-dynamic-vehicle-for-transmitting-and-recording-cytokine-signaling
#16
John L Johnson, Golnaz Vahedi
CD4(+) T cells are critical for the elimination of an immense array of microbial pathogens. Although there are aspects of helper T-cell differentiation that can be modeled as a classic cell-fate commitment, CD4(+) T cells also maintain considerable flexibility in their transcriptional program. Here, we present an overview of chromatin biology during cellular reprogramming and, within this context, envision how the scope of cellular reprogramming may be expanded to further our understanding of the controversy surrounding CD4(+) T lymphocyte plasticity or determinism...
April 21, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28431857/modeling-human-infertility-with-pluripotent-stem-cells
#17
Di Chen, Joanna J Gell, Yu Tao, Enrique Sosa, Amander T Clark
Human fertility is dependent upon the correct establishment and differentiation of the germline. This is because no other cell type in the body is capable of passing a genome and epigenome from parent to child. Terminally differentiated germline cells in the adult testis and ovary are called gametes. However, the initial specification of germline cells occurs in the embryo around the time of gastrulation. Most of our knowledge regarding the cell and molecular events that govern human germline specification involves extrapolating scientific principles from model organisms, most notably the mouse...
April 13, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28431793/alcohol-effects-on-the-epigenome-in-the-germline-role-in-the-inheritance-of-alcohol-related-pathology
#18
REVIEW
Lucy G Chastain, Dipak K Sarkar
Excessive alcohol exposure has severe health consequences, and clinical and animal studies have demonstrated that disruptions in the epigenome of somatic cells, such as those in brain, are an important factor in the development of alcohol-related pathologies, such as alcohol-use disorders (AUDs) and fetal alcohol spectrum disorders (FASDs). It is also well known that alcohol-related health problems are passed down across generations in human populations, but the complete mechanisms for this phenomenon are currently unknown...
March 6, 2017: Alcohol
https://www.readbyqxmd.com/read/28431147/detection-of-epigenetic-mutagens-including-anthracene-derived-compounds-using-yeast-flo1-promoter-gfp-reporter-gene-assay
#19
Kei-Ichi Sugiyama, Hiroko Furusawa, Petr Grúz, Masamitsu Honma
Recently, we have reported that the FLO1-mediated flocculation levels of yeast are affected by an epigenetic mutagen, alizarin. Alizarin promoted flocculation and reduced the bulk levels of histone H3 in yeast cells. Since alizarin has been known to possess carcinogenesis-promoting properties, it is important to estimate the effect of alizarin-related compounds on epigenome as measured by the flocculation of yeast. In this study, we examined the effects of two anthracene-derived compounds other than alizarin on the flocculation level of yeast...
April 20, 2017: Mutagenesis
https://www.readbyqxmd.com/read/28428977/19th-workshop-of-the-international-stroke-genetics-consortium-april-28-29-2016-boston-massachusetts-usa-2016-001-mri-defined-cerebrovascular-genomics-the-charge-consortium
#20
S Debette, Y Saba, D Vojinovic, X Jian, H Adams, G Chauhan, M Sargurupremraj, S Kaffashian, J Ding, J C Bis, P Nyquist, K Mather, C Van Duijn, L J Launer, M A Ikram, H Schmidt, W T Longstreth, M Fornage, S Seshadri
The CHARGE consortium is an investigator-initiated collaboration to facilitate meta-analyses of genome-wide association studies (GWAS) and genomic analyses based on next generation sequencing (NGS), among multiple large and well-phenotyped population-based cohort studies around the world (http://www.chargeconsortium.com). Within the neuro-CHARGE working group, we are presenting an update of ongoing genomic studies on MRI-markers of cerebrovascular disease. Large population-based studies have shown that the burden of cerebrovascular disease extends far beyond that of clinical stroke...
March 2017: Neurology. Genetics
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