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stem cell epigenetics

Fiorella Casamenti, Massimo Stefani
Clinical trials and population studies indicate the healthy virtues of the Mediterranean diet and its main lipid component, extra-virgin olive oil (EVOO). Olive leaves and EVOO contain many phenolics effective against several aging and lifestyle-related diseases, including neurodegeneration, both in animal models and in humans. Recent research has shown that such protection stems from several effects, including (i.) the interference with the aggregation of peptides/proteins found in amyloid diseases, particularly in Alzheimer's and Parkinson's diseases; (ii...
October 20, 2016: Expert Review of Neurotherapeutics
Clara Lopes Novo, Peter J Rugg-Gunn
Pluripotent cells are characterized by a globally open and accessible chromatin organization that is thought to contribute to cellular plasticity and developmental decision-making. We recently identified the pluripotency factor Nanog as a key regulator of this form of chromatin architecture in mouse embryonic stem cells. In particular, we demonstrated that the transcription factors Nanog and Sall1 co-dependently mediate the epigenetic state of pericentromeric heterochromatin to reinforce a more open and accessible organization in pluripotent cells...
October 19, 2016: Nucleus
Sheng-Chieh Lin, Yu-Ting Chou, Shih-Sheng Jiang, Junn-Liang Chang, Chih-Hung Chung, Yu-Rung Kao, I-Shou Chang, Cheng-Wen Wu
Cell differentiation within stem cell lineages can check proliferative potential but nodal pathways that can limit tumor growth are obscure. Here we report that lung cancer cell populations generate phenotypic and oncogenic plasticity via a switch between differentiation programs controlled by SOX2 and SOX9, thus altering proliferative and invasive capabilities. In lung cancer cells, SOX2 bound the EPCAM promoter to induce EpCAM-p21Cip1-cyclin A2 signaling, encouraging cell proliferation as well as barrier properties...
October 7, 2016: Cancer Research
Martino Deidda, Rosalinda Madonna, Ruggiero Mango, Pasquale Pagliaro, Pier P Bassareo, Lucia Cugusi, Silvio Romano, Maria Penco, Francesco Romeo, Giuseppe Mercuro
Despite advances in supportive and protective therapy for myocardial function, heart failure caused by various clinical conditions, including cardiomyopathy due to antineoplastic therapy, remains a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators have been searching for alternative treatments that can effectively repair the damaged heart and permanently restore its function. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as trastuzumab...
May 2016: Journal of Cardiovascular Medicine
Renjing Liu, Kun-Yong Kim, Yong-Wook Jung, In-Hyun Park
DNA methylation is an important epigenetic mark that regulates gene expression. Dnmt1 plays an important role in maintaining DNA methylation patterns on daughter DNA strands. Studies have shed light into the functional role of Dnmt1 regulation in the hematopoietic and epidermal systems. Here we show that Dnmt1 is required for myogenesis. Loss of Dnmt1 results in reduced expression of myogenic genes and defects in myogenic differentiation. We have utilized a conditional knockout mouse approach to examine the functional consequences of Dnmt1 depletion specifically in the developing muscle...
October 18, 2016: Scientific Reports
Christina R Tyler, Matthew T Labrecque, Elizabeth R Solomon, Xun Guo, Andrea M Allan
Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs)...
October 14, 2016: Neurotoxicology and Teratology
Xiang Yuan, Jinyu Kong, Zhikun Ma, Na Li, Ruinuo Jia, Yiwen Liu, Fuyou Zhou, Qimin Zhan, Gang Liu, Shegan Gao
Our studies investigating the existence of tumor-initiating cell (TIC) populations in human esophageal squamous cell carcinoma (ESCC) had identified a subpopulation of cells isolated from ESCC patient-derived tumor specimens marked by an ALDH(bri+) phenotype bear stem cell-like features. Importantly, KDM4C, a histone demethylase was enhanced in ALDH(bri+) subpopulation, suggesting that strategies interfering with KDM4C may be able to target these putative TICs. In the present study, by genetic and chemical means, we demonstrated that, KDM4C blockade selectively decreased the ESCC ALDH(bri+) TICs population in vitro and specifically targeted the TICs in ALDH(bri+)-derived xenograft, retarding engraftment...
October 2016: Neoplasia: An International Journal for Oncology Research
Zahia Hamidouche, Karen Rother, Jens Przybilla, Axel Krinner, Denis Clay, Lydia Hopp, Claire Fabian, Alexandra Stolzing, Hans Binder, Pierre Charbord, Joerg Galle
The molecular mechanisms by which heterogeneity, a major characteristic of stem cells, is achieved are yet unclear. We here study the expression of the membrane stem cell antigen-1 (Sca-1) in mouse bone marrow Mesenchymal Stem Cell (MSC) clones. We show that subpopulations with varying Sca-1 expression profiles regenerate the Sca-1 profile of the mother population within a few days. However, after extensive replication in vitro the expression profiles shift to lower values and the regeneration time increases...
October 13, 2016: Stem Cells
Naoko Irie, M Azim Surani
We recently reported a robust and defined culture system for the specification of human primordial germ cell-like cells (hPGCLCs) from human pluripotent stem cells (hPSCs), both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro (Irie et al. Cell 160: 253-268, 2015). Similar attempts previously produced hPGCLCs from hPSCs at a very low efficiency, and the resulting cells were not fully characterized. A key step, which facilitated efficient hPGCLC specification from hPSCs, was the induction of a "competent" state for PGC fate via the medium containing a cocktail of four inhibitors...
2017: Methods in Molecular Biology
Timothy Alexander Hore, Ferdinand von Meyenn, Mirunalini Ravichandran, Martin Bachman, Gabriella Ficz, David Oxley, Fátima Santos, Shankar Balasubramanian, Tomasz P Jurkowski, Wolf Reik
Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ferdinand von Meyenn, Rebecca V Berrens, Simon Andrews, Fátima Santos, Amanda J Collier, Felix Krueger, Rodrigo Osorno, Wendy Dean, Peter J Rugg-Gunn, Wolf Reik
Primordial germ cell (PGC) development is characterized by global epigenetic remodeling, which resets genomic potential and establishes an epigenetic ground state. Here we recapitulate PGC specification in vitro from naive embryonic stem cells and characterize the early events of epigenetic reprogramming during the formation of the human and mouse germline. Following rapid de novo DNA methylation during priming to epiblast-like cells, methylation is globally erased in PGC-like cells. Repressive chromatin marks (H3K9me2/3) and transposable elements are enriched at demethylation-resistant regions, while active chromatin marks (H3K4me3 or H3K27ac) are more prominent at regions that demethylate faster...
October 10, 2016: Developmental Cell
Prashant S Kota, Mostafa R Naguib, Vivekkumar Patel, Todd K Rosengart
The prospect of genetically reprogramming cardiac fibroblasts into induced cardiomyocytes by using cardio-differentiating transcription factors represents a significant advantage over previous strategies involving stem cell implantation or the delivery of angiogenic factors. Remarkably, intramyocardial administration of cardio-differentiating factors consistently results in 20% to 30% improvements in postinfarct ejection fraction and nearly a 50% reduction in myocardial fibrosis in murine models. Despite these encouraging observations, few breakthroughs have been made in the reprogramming of human cells, which have more rigorous epigenetic constraints and gene regulatory networks that oppose reprogramming...
August 31, 2016: Journal of Thoracic and Cardiovascular Surgery
Katsuto Takenaka
Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera, essential thrombocytosis, and primary myelofibrosis. The JAK2V617F mutation was identified in 2005, followed by the discovery of the JAK2 exon12, MPNW515 mutation, and CALR mutation. About 90% of patients with BCR/ABL negative MPNs have been shown to have one of these driver mutations. In addition, mutations in epigenetic regulators and RNA splicing genes were found to co-exist with driver mutations and to play critical roles in the disease progression of MPNs...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Jun Udagawa, Kodai Hino
Epidemiological studies suggest that exposure to prenatal stressors, including malnutrition, maternal immune activation (MIA), and adverse life events, is associated with increased risks of schizophrenia, autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD). However, the underlying pathophysiological mechanisms are unclear. The first trimester of pregnancy is particularly a vulnerable period. During this period, the self-renewal of neural stem cells and neurogenesis vigorously occur, and synaptic connections are partially formed in the telencephalon...
2016: Nihon Eiseigaku Zasshi. Japanese Journal of Hygiene
Senthilkumar Sivanesan, Aaron Tan, Rebecca Jeyaraj, James Lam, Monica Gole, Antonio Hardan, Keyoumars Ashkan, Jayakumar Rajadas
Autism Spectrum Disorders (ASDs) are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention, and impaired social and communication skills. ASDs are also associated with a number of functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. Although the exact causes of ASDs are currently unknown, it is suggested that genetic, epigenetic and environmental factors play critical roles...
October 7, 2016: World Neurosurgery
Nicola Festuccia, Agnès Dubois, Sandrine Vandormael-Pournin, Elena Gallego Tejeda, Adrien Mouren, Sylvain Bessonnard, Florian Mueller, Caroline Proux, Michel Cohen-Tannoudji, Pablo Navarro
Pluripotent mouse embryonic stem cells maintain their identity throughout virtually infinite cell divisions. This phenomenon, referred to as self-renewal, depends on a network of sequence-specific transcription factors (TFs) and requires daughter cells to accurately reproduce the gene expression pattern of the mother. However, dramatic chromosomal changes take place in mitosis, generally leading to the eviction of TFs from chromatin. Here, we report that Esrrb, a major pluripotency TF, remains bound to key regulatory regions during mitosis...
October 10, 2016: Nature Cell Biology
Patrícia Oliveira, Joana Carvalho, Sara Rocha, Mafalda Azevedo, Inês Reis, Vânia Camilo, Bárbara Sousa, Sofia Valente, Joana Paredes, Raquel Almeida, David Huntsman, Carla Oliveira
Dies1/VISTA induces embryonic stem-cell differentiation, via BMP-pathway, but also acts as inflammation regulator and immune-response modulator. Dies1 inhibition in a melanoma-mouse model led to increased tumour-infiltrating T-cells and decreased tumour growth, emphasizing Dies1 relevance in tumour-microenvironment. Dies1 is involved in cell de/differentiation, inflammation and cancer processes, which mimic those associated with Epithelial-to-Mesenchymal-Transition (EMT). Despite this axis linking Dies1 with EMT and cancer, its expression, modulation and relevance in these contexts is unknown...
October 10, 2016: Scientific Reports
N A Wijetunga, M Pascual, J Tozour, F Delahaye, M Alani, M Adeyeye, A W Wolkoff, A Verma, J M Greally
The predisposition of patients with Hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) involves components of viral infection, inflammation and time. The development of multifocal, genetically distinct tumours is suggestive of a field defect affecting the entire liver. The molecular susceptibility mediating such a field defect is not understood. One potential mediator of long-term cellular reprogramming is heritable (epigenetic) regulation of transcription, exemplified by DNA methylation. We studied epigenetic and transcriptional changes in HCV-infected livers in comparison with control, uninfected livers and HCC, allowing us to identify pre-neoplastic epigenetic and transcriptional events...
October 10, 2016: Oncogene
Sonja Levanat, Maja Sabol, Vesna Musani, Petar Ozretić, Diana Trnski
BACKGROUND: Hedgehog signaling pathway is a developmental pathway mostly inactive in adult tissues, with the exception of stem cells. It is often found upregulated in various tumors, and associated with cancer stem cell maintenance. METHOD: This review focuses on different aspects of Hedgehog activation in tumors, with special emphasis on ovarian tumors and their treatment. RESULTS: Mutations in pathway components lead to a series of developmental malformations and syndromes...
October 6, 2016: Current Pharmaceutical Design
Platonova Natalia, Lesma Elena, Basile Andrea, Bignotto Monica, Garavelli Silvia, Palano Maria Teresa, Moschini Adriana, Neri Antonino, Colombo Michela, Chiaramonte Raffaella
BACKGROUND: Notch is a multifaceted protein that plays a fundamental role in fetal development and tissue homeostasis by directing many cellular functions, including cell growth and differentiation, cell fate determination and regulation of stem cells maintenance. The Notch family consists of four receptors (Notch 1-4) and five ligands (Jagged1-2 and Delta-like 1-3-4) widely expressed in human tissues. Given the crucial contribution of Notch signaling in many physiological processes, it is not surprising that a variety of human malignancies is characterized by a dysregulation of one or more components of this pathway Methods: In this review, we are going to provide a broad overview on the role of Notch pathway in solid and hematological malignancies and a survey on possible Notch-directed therapeutic strategies...
October 6, 2016: Current Pharmaceutical Design
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