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Beatriz Del Blanco, Angel Barco
During development, chromatin changes contribute to establishing and maintaining the distinct gene-expression profiles of each individual cell type in a multicellular organism. This feat is especially remarkable in the human brain considering the sheer number of distinct cell types that make up this organ. This epigenetic programing is sensitive to environmental influences such as the presence of toxicants, diet, temperature, maternal behavior and many other external factors that can lead to sustained differences in neuronal gene expression...
June 15, 2018: Current Opinion in Chemical Biology
A Silva-Palacios, M Ostolga-Chavarría, C Zazueta, M Königsberg
Increase in life-span is commonly related with age-related diseases and with gradual loss of genomic, proteomic and metabolic integrity. Nrf2 (Nuclear factor-erythroid 2-p45 derived factor 2) controls the expression of genes whose products include antioxidant proteins, detoxifying enzymes, drug transporters and numerous cytoprotective proteins. Several experimental approaches have evaluated the potential regulation of the transcription factor Nrf2 to enhance the expression of genes that contend against accumulative oxidative stress and promote healthy aging...
June 15, 2018: Ageing Research Reviews
Benjamin J Halliday, Ryuji Fukuzawa, David M Markie, Richard G Grundy, Jackie L Ludgate, Michael A Black, Jane E Skeen, Robert J Weeks, Daniel R Catchpoole, Aedan G K Roberts, Anthony E Reeve, Ian M Morison
Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing...
June 2018: PLoS Genetics
Judit Symmank, Cathrin Bayer, Christiane Schmidt, Anne Hahn, Daniel Pensold, Geraldine Zimmer
Epigenetic mechanisms of gene regulation, including DNA methylation and histone modifications, call increasing attention in the context of development and human health. Thereby, interactions between DNA methylating enzymes and histone modifications tremendously multiply the spectrum of potential regulatory functions. Epigenetic networks are critically involved in the establishment and functionality of neuronal circuits that are composed of gamma-aminobutyric acid (GABA)-positive inhibitory interneurons and excitatory principal neurons in the cerebral cortex...
June 18, 2018: Epigenetics: Official Journal of the DNA Methylation Society
Shota Nishitani, Sasha E Parets, Brian W Haas, Alicia K Smith
Saliva is a non-invasive, easily accessible tissue, which is regularly collected in large epidemiological studies to examine genetic questions. Recently, it is becoming more common to use saliva to assess DNA methylation. However, DNA extracted from saliva is a mixture of both bacterial and human DNA derived from epithelial and immune cells in the mouth. Thus, there are unique challenges to using salivary DNA in methylation studies that can influence data quality. This study assesses: (1) quantification of human DNA after extraction; (2) delineation of human and bacterial DNA; (3) bisulfite conversion (BSC); (4) quantification of BSC DNA; (5) PCR amplification of BSC DNA from saliva and; (6) quantitation of DNA methylation with a targeted assay...
June 18, 2018: Epigenetics: Official Journal of the DNA Methylation Society
Z Jiang, J Lin, H Dong, X Zheng, S L Marjani, J Duan, Z Ouyang, J Chen, X C Tian
DNA methylation is an important epigenetic modification that undergoes dynamic changes in mammalian embryogenesis, during which both parental genomes are reprogrammed. Despite the many immunostaining studies that have assessed global methylation, the gene-specific DNA methylation patterns in bovine preimplantation embryos are unknown. Using reduced representation bisulfite sequencing, we determined genome-scale DNA methylation of bovine sperm and individual in vivo developed oocytes and preimplantation embryos...
June 14, 2018: Biology of Reproduction
Ya Wang, Andrew E Teschendorff, Martin Widschwendter, Shuang Wang
DNA methylation plays an essential role in cancer. Differential variability (DV) in cancer was recently observed that contributes to cancer heterogeneity and has been shown to be crucial in detecting epigenetic field defects, DNA methylation alterations happening early in carcinogenesis. As neighboring CpG sites are highly correlated, here, we present a new method to detect differentially methylated regions (DMRs) that uses combined signals from differential methylation and DV between sample groups. We demonstrated in simulation studies the superior performance of the new method than existing methods that use only one type of signals when true DMRs have both...
August 18, 2017: Briefings in Bioinformatics
Sunmi Seok, Young-Chae Kim, Sangwon Byun, Sunge Choi, Zhen Xiao, Naoki Iwamori, Yang Zhang, Chaochen Wang, Jian Ma, Kai Ge, Byron Kemper, Jongsook Kim Kemper
Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid β-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial β-oxidation, but not gluconeogenic, genes during fasting...
June 18, 2018: Journal of Clinical Investigation
Dionna M Kasper, Stefania Nicoli
Purpose of the Review: Blood specification is a highly dynamic process, whereby committed hemogenic endothelial cells (ECs) progressively transdifferentiate into multipotent, self-renewing hematopoietic stem cells (HSCs). Massive changes in gene expression must occur to switch cell identity, however the factors that mediate such an effect were a mystery until recently. This review summarizes the higher-order mechanisms involved in endothelial to hematopoietic reprogramming identified thus far...
March 2018: Current Stem Cell Reports
Yiting Wang, Huanbin Wang, Han Yao, Chushu Li, Jing-Yuan Fang, Jie Xu
Immune checkpoint blockade therapies (ICBTs) targeting programmed cell death 1 (PD-1) and its ligand programmed death ligand-1 (PD-L1/B7-H1/CD274) have exhibited momentous clinical benefits and durable responses in multiple tumor types. However, primary resistance is found in considerable number of cancer patients, and most responders eventually develop acquired resistance to ICBT. To tackle these challenges, it is essential to understand how PD-L1 is controlled by cancer cells to evade immune surveillance...
2018: Frontiers in Pharmacology
A AlFakeeh, C Brezden-Masley
Endocrine therapy, a major modality in the treatment of hormone receptor (hr)-positive breast cancer (bca), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in bca is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)-targeted therapy. The resistance pathways involve extensive cross-talk between er and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (her2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways-most notably pi3k/akt/mtor and mapk...
June 2018: Current Oncology
Kenjiro Adachi, Wolfgang Kopp, Guangming Wu, Sandra Heising, Boris Greber, Martin Stehling, Marcos J Araúzo-Bravo, Stefan T Boerno, Bernd Timmermann, Martin Vingron, Hans R Schöler
Transcription factor (TF)-mediated reprogramming to pluripotency is a slow and inefficient process, because most pluripotency TFs fail to access relevant target sites in a refractory chromatin environment. It is still unclear how TFs actually orchestrate the opening of repressive chromatin during the long latency period of reprogramming. Here, we show that the orphan nuclear receptor Esrrb plays a pioneering role in recruiting the core pluripotency factors Oct4, Sox2, and Nanog to inactive enhancers in closed chromatin during the reprogramming of epiblast stem cells...
June 11, 2018: Cell Stem Cell
Yoav Voichek, Karin Mittelman, Yulia Gordon, Raz Bar-Ziv, David Lifshitz Smit, Rom Shenhav, Naama Barkai
DNA replication introduces a dosage imbalance between early and late replicating genes. In budding yeast, buffering gene expression against this imbalance depends on marking replicated DNA by H3K56 acetylation (H3K56ac). Whether additional processes are required for suppressing transcription from H3K56ac-labeled DNA remains unknown. Here, using a database-guided candidate screen, we find that COMPASS, the H3K4 methyltransferase, and its upstream effector, PAF1C, act downstream of H3K56ac to buffer expression...
June 5, 2018: Molecular Cell
Hari R Singh
The epigenome editing framework provides an engineering approach to explore chromatin-based gene expression mechanisms. However, therapeutic utility of epigenetic editing-based systems has been lacking. A report in Cell (Liu et. al., 2018) shows that epigenetic editors can revert abnormal heterochromatin formation at the gene promoter leading to restoration of FMR1 gene expression, functionally rescuing fragile X syndrome (FXS), an otherwise unamenable genetic disorder.
June 14, 2018: Trends in Biochemical Sciences
David Y Takeda, Sándor Spisák, Ji-Heui Seo, Connor Bell, Edward O'Connor, Keegan Korthauer, Dezső Ribli, István Csabai, Norbert Solymosi, Zoltán Szállási, David R Stillman, Paloma Cejas, Xintao Qiu, Henry W Long, Viktória Tisza, Pier Vitale Nuzzo, Mersedeh Rohanizadegan, Mark M Pomerantz, William C Hahn, Matthew L Freedman
Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide...
June 9, 2018: Cell
B Siddeek, C Mauduit, C Yzydorczyk, M Benahmed, U Simeoni
Epidemiological and experimental observations tend to prove that environment, lifestyle or nutritional challenges influence heart functions together with genetic factors. Furthermore, when occurring during sensitive windows of heart development, these environmental challenges can induce an 'altered programming' of heart development and shape the future heart disease risk. In the etiology of heart diseases driven by environmental challenges, epigenetics has been highlighted as an underlying mechanism, constituting a bridge between environment and heart health...
June 18, 2018: Journal of Developmental Origins of Health and Disease
Ilaria Panzeri, John Andrew Pospisilik
BACKGROUND: The alarming rise of obesity and its associated comorbidities represents a medical burden and a major global health and economic issue. Understanding etiological mechanisms underpinning susceptibility and therapeutic response is of primary importance. Obesity, diabetes, and metabolic diseases are complex trait disorders with only partial genetic heritability, indicating important roles for environmental programing and epigenetic effects. SCOPE OF THE REVIEW: We will highlight some of the reasons for the scarce predictability of metabolic diseases...
May 18, 2018: Molecular Metabolism
Li Liu, Xiaoyan Wu, Huihui Xu, Liming Yu, Xinjian Zhang, Luyang Li, Jianliang Jin, Tao Zhang, Yong Xu
A host of pathogenic factors induce acute kidney injury (AKI) leading to insufficiencies of renal function. In the present study we evaluated the role of myocardin-related transcription factor A (MRTF-A) in the pathogenesis of AKI. We report that systemic deletion of MRTF-A or inhibition of MRTF-A activity with CCG-1423 significantly attenuated AKI in mice induced by either ischemia-reperfusion or LPS injection. Of note, MRTF-A deficiency or suppression resulted in diminished renal ROS production in AKI models with down-regulation of NAPDH oxdiase 1 (NOX1) and NOX4 expression...
June 14, 2018: Biochimica et Biophysica Acta
Annette E Neele, Marion J J Gijbels, Saskia van der Velden, Marten A Hoeksema, Marieke C S Boshuizen, Koen H M Prange, Hung-Jen Chen, Jan Van den Bossche, Cindy P P A van Roomen, Annelie Shami, Johannes H M Levels, Jeffrey Kroon, Tina Lucas, Stefanie Dimmeler, Esther Lutgens, Menno P J de Winther
BACKGROUND AND AIMS: Atherosclerosis is a lipid-driven chronic inflammatory disorder of the arteries, and monocytes and macrophages play a central role in this process. Within the atherosclerotic lesion, macrophages can scavenge modified lipids and become the so-called foam cells. We previously reported that the epigenetic enzyme Kdm6b (also known as Jmjd3) controls the pro-fibrotic transcriptional profile of peritoneal foam cells. Given the importance of these cells in atherosclerosis, we now studied the effect of myeloid Kdm6b on disease progression...
June 1, 2018: Atherosclerosis
Kazuki Kurimoto, Mitinori Saitou
Germ cells undergo epigenome reprogramming for proper development of the next generation. The realization of germ cell derivation from human and mouse pluripotent stem cells offers unprecedented opportunity for investigation of germline development. Primordial germ cells reconstituted in vitro (PGC-like cells [PGCLCs]) show progressive dilution of genomic DNA methylation, tightly linked with chromatin remodeling, during their specification. PGCLCs can be further expanded by plane culture, allowing maintenance of the gene-expression profiles of early PGCs and continuance of the DNA methylation erasure, thereby establishing an epigenetic `blank slate'...
June 13, 2018: Current Opinion in Genetics & Development
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