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reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk

MOLECULAR ENDOCRINOLOGY 2016年第8期30卷 856-871页

作者： Wang, Quan Trevino, Lindsey S. Wong, Rebecca Lee Yean Medvedovic, Mario Chen, Jing Ho, Shuk-mei Shen, Jianjun Foulds, Charles E. Coarfa, Cristian O'Malley, Bert W. Shilatifard, Ali Walker, Cheryl L. Texas A&M Univ Syst Hlth Sci Ctr Inst Biosci & Technol Ctr Translat Canc Res 2121 West Holcombe Blvd Houston TX 77030 USA Baylor Coll Med Dept Mol & Cellular Biol Houston TX 77030 USA Univ Cincinnati Coll Med Dept Environm Hlth Cincinnati OH 45267 USA Univ Cincinnati Coll Med Dept Environm Hlth Cincinnati OH 45267 USA Univ Texas MD Anderson Canc Ctr Dept Epigenet & Mol Carcinogenesis Smithville TX 78957 USA Northwestern Univ Dept Biochem & Mol Genet Feinberg Sch Med Chicago IL 60611 USA

Tissue and organ development is a time of exquisite sensitivity to environmental exposures, which can reprogram developing tissues to increase susceptibility to adult diseases, including cancer. In the developing prostate, even brief exposure to endocrine-disrupting chemicals (EDCs) can increase risk for developing cancer in adulthood, with disruption of the epigenome thought to play a key role in this developmental reprogramming. We find that EDC-induced nongenomic phosphoinositide 3-kinase;(PI3K) signaling engages the histone methyltransferase mixed-lineage leukemia 1 (MLL1), responsible for the histone H3 lysine 4 trimethylation (H3K4me3) active epigenetic mark, to increase cleavage and formation of active MLL1 dimers. In the developing prostate, EDC-induced MLL1 activation increased H3K4me3 at genes associated with prostate cancer, with increased H3K4me3 and elevated basal and hormone-induced expression of reprogrammed genes persisting into adulthood. These data identify a mechanism for MLL1 activation that is vulnerable to disruption by environmental exposures, and link MLL1 activation by EDCs to developmental reprogramming of genes involved in prostate cancer.

关键词： adulthood Prostate Cancer KMT2A gene cancer risk histone methyltransferase adult disease Organogenesis Environmental Exposure reprogramming

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reprogramming: faithful reporters

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NATURE METHODS 2012年第3期9卷 231-234页

作者： Baker, Monya Nature and Nature Methods

AffiliationsMonya Baker is technology editor for Nature and Nature Methods Corresponding authorCorrespondence to:

关键词： Cytological techniques Pluripotent stem cells reprogramming

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reprogramming Stromal Cells from the Urinary Tract and Prostate: A Trip to Pluripotency and Back?

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EUROPEAN UROLOGY 2013年第5期64卷 762-764页

作者： Wezel, Felix Southgate, Jennifer Univ York Dept Biol Jack Birch Unit Mol Carcinogenesis York YO10 5DD N Yorkshire England Univ Med Ctr Mannheim Dept Urol Mannheim Germany

The discovery by Takahashi and Yamanaka in 2006 that they could revert somatic cells to a pluripotent phenotype by overexpressing a limited number of defined reprogram-ming factors [1] has had a major impact on the stem cell research community. These so-called induced pluripotent stem (iPS) cells are very similar to embryonic-derived stem cells (ESCs) with respect to gene expression profile, proliferation, and pluripotent differentiation potential. The relative simplicity of the reprogramming technique, coupled with the ethical superiority over ESCs and the potential to produce a ready supply of patient-specific autologous cells arguably make iPS cells the most promising stem cell source for regenerative medicine.

关键词： Stem Cells Stem Cell Research differentiation potential Stromal Cells Regenerative Medicine Diploid Cell Urinary Tract reprogramming major impact pluripotency Induced Pluripotent Stem Cells

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reprogramming of somatic cells induced by fusion of embryonic stem cells using hemagglutinating virus of Japan envelope (HVJ-E)

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2010年第4期394卷 1053-1057页

作者： Yue, Xiao-shan Fujishiro, Masako Toyoda, Masashi Akaike, Toshihiro Ito, Yoshihiro RIKEN Adv Sci Inst Nano Med Engn Lab Wako Saitama 3510198 Japan Tokyo Inst Technol Grad Sch Biosci & Technol Dept Biomol Engn Midori Ku Yokohama Kanagawa 2268501 Japan Natl Inst Child Hlth & Dev Dept Reprod Biol Setagaya Ku Tokyo 1578535 Japan

In this research, hemagglutinating virus of Japan envelope (HVJ-E) was used to reprogram somatic cells by fusion with mouse embryonic stem (ES) cells. Neomycin-resistant mouse embryonic fibroblasts (MEFs) were used as somatic cells. Nanog-overexpressing puromycin-resistant EB3 cells were used as mouse ES cells. These two cells were fused by exposing to HVJ-E and the generated fusion cells were selected by puromycin and G418 to get the stable fusion cell line. The fusion cells form colonies in feeder-free culture system. Microsatellite analysis of the fusion cells showed that they possessed genes from both ES cells and fibroblasts. The fusion cells were tetraploid, had alkali phosphatase activity, and expressed stem cell marker genes such as Pou5f1. Nanog, and Sox2, but not the fibroblast cell marker genes such as Col1a1 and Col1a2. The pluripotency of fusion cells was confirmed by their expression of marker genes for all the three germ layers after differentiation induction, and by their ability to form teratoma which contained all the three primary layers. Our results show that HVJ-E can be used as a fusion reagent for reprogramming of somatic cells. Crown Copyright (C) 2010 Published by Elsevier Inc. All rights reserved.

关键词： reprogramming Cell fusion ES cell HVJ-envelope

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reprogramming of the MHC-I and Its Regulation by NFκB in Human-Induced Pluripotent Stem Cells

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STEM CELLS 2012年第12期30卷 2700-2708页

作者： Pick, Marjorie Ronen, Daniel Yanuka, Ofra Benvenisty, Nissim Hebrew Univ Jerusalem Inst Life Sci Dept Genet Stem Cell Unit IL-91904 Jerusalem Israel Hadassah Hebrew Univ Med Ctr Sharett Inst Dept Hematol Jerusalem Israel

The immunogenicity of human pluripotent stem cells plays a major role in their potential use in the clinic. We show that, during their reprogramming, human-induced pluripotent stem (iPS) cells downregulate expression of human leukocyte antigen (HLA)-A/B/C and beta 2 microglobulin (beta 2M), the two components of major histocompatibility complex-I (MHC-I). MHC-I expression in iPS cells can be restored by differentiation or treatment with interferon-gamma (IFN gamma). To analyze the molecular mechanisms that regulate the expression of the MHC-I molecules in human iPS cells, we searched for correlation between the expression of HLA-A/B/C and beta 2M and the expression of transcription factors that bind to the promoter of these genes. Our results show a significant positive correlation between MHC-I expression and expression of the nuclear factors, nuclear factor kappa B 1 (NF kappa B1) and RelA, at the levels of RNA, protein and was confirmed by chromatin binding. Concordantly, we detected robust levels of NF kappa B1 and RelA proteins in the nucleus of somatic cells but not in the iPS cell derived from them. Overexpression of NF kappa B1 and RelA in undifferentiated pluripotent stem cells led to induction in expression of MHC-I, whereas silencing NF kappa B1 and RelA by small hairpin RNA decreased the expression of beta 2M after IFN gamma treatment. Our data point to the critical role of NF kappa B proteins in regulating the MHC-I expression in human pluripotent stem cells. STEM CELLS 2012;30: 2700-2708

关键词： Induced pluripotent stem cells reprogramming Pluripotent stem cells Immunogenicity

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reprogramming of carbon metabolism by the transcriptional activators AcuK and AcuM in Aspergillus nidulans

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MOLECULAR MICROBIOLOGY 2012年第5期84卷 942-964页

作者： Suzuki, Yumi Murray, Sandra L. Wong, Koon Ho Davis, Meryl A. Hynes, Michael J. Univ Melbourne Dept Genet Melbourne Vic 3010 Australia Harvard Univ Sch Med Dept Biol Chem & Mol Pharmacol Boston MA 02115 USA

The ability of fungi to use carbon sources metabolized via the TCA cycle requires gluconeogenesis. In Aspergillus nidulans the AcuK and AcuM transcription factors regulate the expression of the gluconeogenic genes acuF, encoding phosphoenolpyruvate carboxykinase, and acuG, encoding fructose-1,6-bisphosphatase. Expressed proteins containing the AcuK/AcuM N-terminal DNA-binding domains bind together in vitro to motifs containing repeats of CGG separated by seven bases (CCGN7CCG) and the functionality of these sequences was verified in vivo by acuFlacZ reporter studies. Chromatin immunoprecipitation analysis showed inter-dependent DNA binding of the proteins to the promoters of gluconeogenic genes in vivo independent of the carbon source. Deletion of the mdhC gene encoding a cytoplasmic/peroxisomal malate dehydrogenase showed that this activity is not essential for gluconeogenesis and indicated that induction of AcuK/AcuM regulated genes might result from malate accumulation. Deletion of the gene for the alternative oxidase did not affect growth on gluconeogenic carbon sources;however, expression was absolutely dependent on AcuK and AcuM. Orthologues of AcuK and AcuM, are present in a wide range of fungal taxa and the CCGN7CCG motif is present in the 5' of many genes involved in gluconeogenesis indicating a fundamental role for these transcription factors in reprogramming fungal carbon metabolism.

关键词： malate dehydrogenase reprogramming Aspergillus nidulans CARBON SOURCES Gluconeogenesis Transcription Factors Citric Acid Cycle carbon metabolism alternative oxidase Chromatin Immunoprecipitation

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reprogramming- and pluripotency-associated membrane proteins in mouse stem cells revealed by label-free quantitative proteomics

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JOURNAL OF PROTEOMICS 2013年 86卷 70-84页

作者： Hao, Jie Li, Wei Dan, Jiameng Ye, Xiaoying Wang, Fang Zeng, Xinhai Wang, Lei Wang, Huiyong Cheng, Yang Liu, Lin Shui, Wenqing Nankai Univ Coll Life Sci Tianjin State Lab Prot Sci Tianjin 300071 Peoples R China Tianjin Joint Acad Biotechnol & Med High Throughput Mol Drug Discovery Ctr Tianjin 300457 Peoples R China ZhongXin Biotechnol Shanghai Co Ltd Shanghai 200235 Peoples R China

Induced pluripotent stem cells (iPSCs), derived from somatic cells and functionally very similar to embryonic stem cells (ESCs), are at the center stage of intense research in regenerative medicine. We carried out the first membrane proteomic profiling of mouse iPSCs, in comparison with ESCs and adult mouse tail tip fibroblasts (TTFs) from which iPSCs were generated. Using a proteomic workflow combining membrane fractionation, SDS-PAGE separation and nanoUPLC-MSE technology, we identified 673, 679 and 682 non-redundant proteins from mouse iPSC, ESC and TTF membrane fractions, respectively. Label-free quantitation revealed 155 reprogramming-associated and 128 pluripotency-associated transmembrane proteins. Furthermore, a small group of 23 membrane proteins mainly involved in amino acid/glucose/ion transport, membrane fusion and vesicular trafficking were found potentially regulated between miPSCs and mESCs. Expression changes of selected proteins were verified by qPCR, western blot and/or immunofluorescence analyses in a wider array Of cell types. Notably, epithelial cell adhesion molecules, glucose transporters 1 and 3, transferrin receptor and several nuclear membrane-associated components were highly expressed in both iPSCs and ESCs, relative to TTFs. Moreover, knock-down of glucose transporter 3 in ESCs impaired the beating function of ESC-derived cardiomyocytes, suggesting its potential role in mediating stem cell differentiation. Biological significance This study constitutes a membrane proteomic resource for murine iPSCs and ESCs, and offers a comparison between pluripotent stem cells and fibroblasts in the proteomic landscape. An integrated proteomics platform combining technologies of membrane fractionation: LC-MSE analysis and label-free quantitation was developed to identify membrane proteins with their abundances related to reprogramming of fibroblasts or maintenance of stem cell pluripotency. The high similarity in the membrane proteomic patterns between

关键词： Induced pluripotent stem cell (iPSC) Embryonic stem cell (ESC) reprogramming Stem cell pluripotency Membrane proteomics Label-free quantitation

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reprogramming of human somatic cells by bacteria

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DEVELOPMENT GROWTH & DIFFERENTIATION 2015年第4期57卷 305-312页

作者： Ito, Naofumi Ohta, Kunimasa Kumamoto Univ Fac Life Sci Div Dev Neurobiol Chuo Ku Kumamoto 8608556 Japan

In general, it had been believed that the cell fate restriction of terminally differentiated somatic cells was irreversible. In 1952, somatic cell nuclear transfer (SCNT) was introduced to study early embryonic development in frogs. So far, various mammalian species have been successfully cloned using the SCNT technique, though its efficiency is very low. Embryonic stem (ES) cells were the first pluripotent cells to be isolated from an embryo and have a powerful potential to differentiate into more than 260 types of cells. The generation of induced pluripotent stem (iPS) cells was a breakthrough in stem cell research, and the use of these iPS cells has solved problems such as low efficiency and cell fate restriction. These cells have since been used for clinical application, disease investigation, and drug selection. As it is widely accepted that the endosymbiosis of Archaea into eukaryotic ancestors resulted in the generation of eukaryotic cells, we examined whether bacterial infection could alter host cell fate. We previously showed that when human dermal fibroblast (HDF) cells were incorporated with lactic acid bacteria (LAB), the LAB-incorporated HDF cells formed clusters and expressed a subset of common pluripotent markers. Moreover, LAB-incorporated cell clusters could differentiate into cells derived from each of the three germinal layers both in vivo and in vitro, indicating successful reprogramming of host HDF cells by LAB. In the current review, we introduce the existing examples of cellular reprogramming by bacteria and discuss their nuclear reprogramming mechanisms.

关键词： bacteria eukaryotic cells multipotency reprogramming

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reprogramming aging through DOT1L inhibition

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CELL CYCLE 2015年第21期14卷 3345-3346页

作者： Soria-Valles, Clara Osorio, Fernando G. Lopez-Otin, Carlos Univ Oviedo Fac Med Inst Univ Oncol IUOPA Dept Bioquim & Biol Mol Oviedo Spain

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reprogramming of cancer stem cells into non-tumorigenic cells using stem cell exosomes for cancer therapy

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2019年第3期512卷 511-516页

作者： Lee, Kyoung Soo Choi, Ji Suk Cho, Yong Woo Hanyang Univ ERICA Dept Mat Sci & Chem Engn Ansan 426791 Gyeonggi Do South Korea Exostemtech Inc Ansan 15588 Gyeonggi Do South Korea

Cancer stem cells (CSCs) are a small population of cells with stem cell-like properties found in tumors. CSCs are closely associated with tumor heterogeneity, which influences tumor progress, metastasis, and drug resistance. Here, we propose a concept to enhance efficacy of cancer therapy through CSC reprogramming into non-tumorigenic cells using stem cell -derived exosomes with osteoinductive potential. We hypothesized that exosomes derived from osteogenic differentiating human adipose-derived stem cells (0D-EX0s) contain specific cargos capable of inducing osteogenic differentiation of CSCs. Quantitative RT-PCR analysis revealed that OD-EXO5 enhanced the expression of osteogenic-related genes, such as alkaline phosphatase (ALPL), osteocalcin (BGLAP), and runt-related transcription factor 2 (RUNX2). In addition, expression of drug-resistance genes such as ATP binding cassette (ABC) transporter, the breast cancer gene family (BCRA1 and BCRA2), and the ErbB gene family were significantly decreased in OD-EXO-treated CSCs. Our findings suggest that OD-EXOs function as a biochemical cue for CSC reprogramming and contribute to overcoming therapeutic resistance. (C) 2019 Elsevier Inc. All rights reserved.

关键词： Exosomes Cancer stem cells reprogramming Drug resistance

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