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Vershkov, D.; Benvenisty, N. |
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Title |
Human pluripotent stem cells in modeling human disorders: the case of fragile X syndrome |
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Journal Article |
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Year |
2017 |
Publication |
Regenerative Medicine |
Abbreviated Journal |
Regen Med |
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12 |
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1 |
Pages |
53-68 |
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Keywords |
disease modeling; drug discovery; embryonic stem cells; fragile X syndrome; human pluripotent stem cells; neural differentiation |
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Abstract |
Human pluripotent stem cells (PSCs) generated from affected blastocysts or from patient-derived somatic cells are an emerging platform for disease modeling and drug discovery. Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, was one of the first disorders modeled in both embryonic stem cells and induced PCSs and can serve as an exemplary case for the utilization of human PSCs in the study of human diseases. Over the past decade, FXS-PSCs have been used to address the fundamental questions regarding the pathophysiology of FXS. In this review we summarize the methodologies for generation of FXS-PSCs, discuss their advantages and disadvantages compared with existing modeling systems and describe their utilization in the study of FXS pathogenesis and in the development of targeted treatment. |
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The Azrieli Center for Stem Cells & Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel |
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1746-0751 |
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PMID:27900874 |
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ref @ user @ |
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95909 |
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Li, M.; Zhao, H.; Ananiev, G.E.; Musser, M.T.; Ness, K.H.; Maglaque, D.L.; Saha, K.; Bhattacharyya, A.; Zhao, X. |
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Title |
Establishment of Reporter Lines for Detecting Fragile X Mental Retardation (FMR1) Gene Reactivation in Human Neural Cells |
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Journal Article |
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Year |
2017 |
Publication |
Stem Cells (Dayton, Ohio) |
Abbreviated Journal |
Stem Cells |
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35 |
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1 |
Pages |
158-169 |
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Drug discovery; Fmr1; Fmrp; Fragile X syndrome; High throughput; Induced pluripotent stem cells; Luciferase |
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Abstract |
Human patient-derived induced pluripotent stem cells (hiPSCs) provide unique opportunities for disease modeling and drug development. However, adapting hiPSCs or their differentiated progenies to high throughput assays for phenotyping or drug screening has been challenging. Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a major genetic cause of autism. FXS is caused by mutational trinucleotide expansion in the FMR1 gene leading to hypermethylation and gene silencing. One potential therapeutic strategy is to reactivate the silenced FMR1 gene, which has been attempted using both candidate chemicals and cell-based screening. However, molecules that effectively reactivate the silenced FMR1 gene are yet to be identified; therefore, a high throughput unbiased screen is needed. Here we demonstrate the creation of a robust FMR1-Nluc reporter hiPSC line by knocking in a Nano luciferase (Nluc) gene into the endogenous human FMR1 gene using the CRISPR/Cas9 genome editing method. We confirmed that luciferase activities faithfully report FMR1 gene expression levels and showed that neural progenitor cells derived from this line could be optimized for high throughput screening. The FMR1-Nluc reporter line is a good resource for drug screening as well as for testing potential genetic reactivation strategies. In addition, our data provide valuable information for the generation of knockin human iPSC reporter lines for disease modeling, drug screening, and mechanistic studies. Stem Cells 2017;35:158-169. |
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Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin, USA |
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1066-5099 |
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PMID:27422057 |
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95937 |
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Fogel, O.; Richard-Miceli, C.; Tost, J. |
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Title |
Epigenetic Changes in Chronic Inflammatory Diseases |
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Journal Article |
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2017 |
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Advances in Protein Chemistry and Structural Biology |
Abbreviated Journal |
Adv Protein Chem Struct Biol |
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106 |
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139-189 |
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Behcet's disease; Crohn's disease; DNA methylation; Ewas; Epigenetics; Histone modifications; Inflammatory bowel disease; Psoriasis; Spondyloarthritis; Ulcerative colitis |
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The number of people diagnosed with chronic inflammatory diseases has increased noteworthy in the last 40 years. Spondyloarthritis (SpA), inflammatory bowel diseases (IBD), and psoriasis are the most frequent chronic inflammatory diseases, resulting from a combination of genetic predisposition and environmental factors. Epigenetic modifications include DNA methylation, histone modifications, and small and long noncoding RNAs. They are influenced by environmental exposure, life-style, and aging and have recently been shown to be altered in many complex diseases including inflammatory diseases. While epigenetic modifications have been well characterized in other diseases such as cancer and autoimmune diseases, knowledge on changes in inflammatory diseases is lagging behind with some disease-specific differences. While the DNA methylation profile of different cell types in patients with IBD has been relatively well described, less is known on changes implicated in psoriasis, and no systematic genome-wide studies have so far been performed in SpA. In this chapter, we review in detail the reported changes in patterns of DNA methylation and posttranslational histone modifications in chronic inflammatory diseases highlighting potential connections between disease-associated pathophysiological changes such as the dysbiosis of the microbiome or genetic variations associated with disease susceptibility and the epigenome. We also discuss important parameters of meaningful epigenetic studies such as the use of well defined, disease-relevant cell populations, and elude on the potential future of engineering of the epigenome in inflammatory diseases. |
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Laboratory for Epigenetics and Environment, Centre National de Genotypage, CEA-Institut de Genomique, Evry, France. Electronic address: tost@cng.fr |
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1876-1623 |
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PMID:28057210 |
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96374 |
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Tahara, T.; Hirata, I.; Nakano, N.; Nagasaka, M.; Nakagawa, Y.; Shibata, T.; Ohmiya, N. |
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Comprehensive DNA Methylation Profiling of Inflammatory Mucosa in Ulcerative Colitis |
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Journal Article |
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2017 |
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Inflammatory Bowel Diseases |
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Inflamm Bowel Dis |
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23 |
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1 |
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165-173 |
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INTRODUCTION: Aberrant DNA methylation frequently occurs in the inflammatory mucosa in ulcerative colitis (UC) and is involved in UC-related tumorigenesis. We performed comprehensive DNA methylation profiling of the promoter regions of the inflamed rectal mucosae of patients with UC. DESIGN: The methylation status of the promoter CpG islands (CGIs) of 45 cancer/inflammation or age-related candidate genes and the LINE1 repetitive element were examined in the colonic mucosae of 84 cancer-free patients with UC by bisulfite pyrosequencing. Methylation status of selected genes (DPYS, N33, MIR1247, GSTP1, and SOX11) was also determined in 14 neoplastic lesions (5 with high-grade dysplasia and 9 with carcinoma) and 8 adjacent tissues derived from 12 patients. An Infinium HumanMethylation450 BeadChip array was used to characterize the methylation status of >450,000 CpG sites for 10 patients with UC. RESULTS: Clustering analysis based on the methylation status of the candidate genes clearly distinguished the inflammatory samples from the noninflammatory samples. The hypermethylation of the promoter CGIs strongly correlated with increased disease duration, which is a known risk factor for the development of colon cancer. Genome-wide methylation analyses revealed a high rate of hypermethylation in the severe phenotype of UC, particularly at the CGIs. Exclusively hypermethylated promoter CGIs in the severe phenotypes were significantly related to genes involved in biosynthetic processes, the regulation of metabolic processes, and nitrogen compound metabolic processes. CONCLUSION: Our findings suggest the potential utility of DNA methylation as a molecular marker and therapeutic target for UC-related tumorigenesis. |
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*Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan; and daggerDepartment of Gastroenterology, Tanimukai Hospital Japan, Nishinomiya, Japan |
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1078-0998 |
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PMID:27930411 |
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96375 |
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Heffernan, J.M.; McNamara, J.B.; Borwege, S.; Vernon, B.L.; Sanai, N.; Mehta, S.; Sirianni, R.W. |
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PNIPAAm-co-Jeffamine(R) (PNJ) scaffolds as in vitro models for niche enrichment of glioblastoma stem-like cells |
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Journal Article |
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2017 |
Publication |
Biomaterials |
Abbreviated Journal |
Biomaterials |
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143 |
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149-158 |
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Brain tumor initiating cells; Cancer stem cells; Radioresistance; Temperature responsive polymer scaffolds; Tissue engineering |
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Glioblastoma (GBM) is the most common adult primary brain tumor, and the 5-year survival rate is less than 5%. GBM malignancy is driven in part by a population of GBM stem-like cells (GSCs) that exhibit indefinite self-renewal capacity, multipotent differentiation, expression of neural stem cell markers, and resistance to conventional treatments. GSCs are enriched in specialized niche microenvironments that regulate stem phenotypes and support GSC radioresistance. Therefore, identifying GSC-niche interactions that regulate stem phenotypes may present a unique target for disrupting the maintenance and persistence of this treatment resistant population. In this work, we engineered 3D scaffolds from temperature responsive poly(N-isopropylacrylamide-co-Jeffamine M-1000(R) acrylamide), or PNJ copolymers, as a platform for enriching stem-specific phenotypes in two molecularly distinct human patient-derived GSC cell lines. Notably, we observed that, compared to conventional neurosphere cultures, PNJ cultured GSCs maintained multipotency and exhibited enhanced self-renewal capacity. Concurrent increases in expression of proteins known to regulate self-renewal, invasion, and stem maintenance in GSCs (NESTIN, EGFR, CD44) suggest that PNJ scaffolds effectively enrich the GSC population. We further observed that PNJ cultured GSCs exhibited increased resistance to radiation treatment compared to GSCs cultured in standard neurosphere conditions. GSC radioresistance is supported in vivo by niche microenvironments, and this remains a significant barrier to effectively treating these highly tumorigenic cells. Taken in sum, these data indicate that the microenvironment created by synthetic PNJ scaffolds models niche enrichment of GSCs in patient-derived GBM cell lines, and presents tissue engineering opportunities for studying clinically important behaviors such as radioresistance in vitro. |
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Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Ave, Phoenix, AZ, 85013, USA; School of Biological and Health Systems Engineering, Arizona State University, PO Box 879709, Tempe, AZ, 85287, USA. Electronic address: rachael.sirianni@dignityhealth.org |
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0142-9612 |
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PMID:28802102 |
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96570 |
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