A Sox2 Distal Enhancer Cluster Regulates Embryonic Stem Cell Differentiation Potential
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Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, and The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, UCSF, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells. -
AIRE Is a Critical Spindle-Associated Protein in Embryonic Stem Cells Bin Gu1, Jean-Philippe Lambert2, Katie Cockburn1, Anne-Claude Gingras2,3, Janet Rossant1,3*
RESEARCH ARTICLE AIRE is a critical spindle-associated protein in embryonic stem cells Bin Gu1, Jean-Philippe Lambert2, Katie Cockburn1, Anne-Claude Gingras2,3, Janet Rossant1,3* 1Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada; 2Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, Canada; 3Department of Molecular Genetics, University of Toronto, Toronto, Canada Abstract Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune tolerance processes, is a critical spindle-associated protein in mouse ES(mES) cells. BioID analysis showed that AIRE associates with spindle-associated proteins in mES cells. Loss of function analysis revealed that Aire was important for centrosome number regulation and spindle pole integrity specifically in mES cells. We also identified the c-terminal LESLL motif as a critical motif for AIRE’s mitotic function. Combined maternal and zygotic knockout further revealed Aire’s critical functions for spindle assembly in preimplantation embryos. These results uncovered a previously unappreciated function for Aire and provide new insights into the biology of stem cell proliferation and potential new angles to understand fertility defects in humans carrying Aire mutations. DOI: 10.7554/eLife.28131.001 *For correspondence: janet. [email protected] Introduction Competing interests: The Self-renewal capability, defined as the ability of cells to proliferate while sustaining differentiation authors declare that no potential, is one of the defining features of stem cells (Martello and Smith, 2014). -
UNIVERSITY of CALIFORNIA, IRVINE Combinatorial Regulation By
UNIVERSITY OF CALIFORNIA, IRVINE Combinatorial regulation by maternal transcription factors during activation of the endoderm gene regulatory network DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Kitt D. Paraiso Dissertation Committee: Professor Ken W.Y. Cho, Chair Associate Professor Olivier Cinquin Professor Thomas Schilling 2018 Chapter 4 © 2017 Elsevier Ltd. © 2018 Kitt D. Paraiso DEDICATION To the incredibly intelligent and talented people, who in one way or another, helped complete this thesis. ii TABLE OF CONTENTS Page LIST OF FIGURES vii LIST OF TABLES ix LIST OF ABBREVIATIONS X ACKNOWLEDGEMENTS xi CURRICULUM VITAE xii ABSTRACT OF THE DISSERTATION xiv CHAPTER 1: Maternal transcription factors during early endoderm formation in 1 Xenopus Transcription factors co-regulate in a cell type-specific manner 2 Otx1 is expressed in a variety of cell lineages 4 Maternal otx1 in the endodermal conteXt 5 Establishment of enhancers by maternal transcription factors 9 Uncovering the endodermal gene regulatory network 12 Zygotic genome activation and temporal control of gene eXpression 14 The role of maternal transcription factors in early development 18 References 19 CHAPTER 2: Assembly of maternal transcription factors initiates the emergence 26 of tissue-specific zygotic cis-regulatory regions Introduction 28 Identification of maternal vegetally-localized transcription factors 31 Vegt and OtX1 combinatorially regulate the endodermal 33 transcriptome iii -
The GATA2 Transcription Factor Negatively Regulates the Proliferation of Neuronal Progenitors
RESEARCH ARTICLE 2155 Development 133, 2155-2165 (2006) doi:10.1242/dev.02377 The GATA2 transcription factor negatively regulates the proliferation of neuronal progenitors Abeer El Wakil*, Cédric Francius*,†, Annie Wolff, Jocelyne Pleau-Varet† and Jeannette Nardelli†,§ Postmitotic neurons are produced from a pool of cycling progenitors in an orderly fashion that requires proper spatial and temporal coordination of proliferation, fate determination, differentiation and morphogenesis. This probably relies on complex interplay between mechanisms that control cell cycle, specification and differentiation. In this respect, we have studied the possible implication of GATA2, a transcription factor that is involved in several neuronal specification pathways, in the control of the proliferation of neural progenitors in the embryonic spinal cord. Using gain- and loss-of-function manipulations, we have shown that Gata2 can drive neural progenitors out of the cycle and, to some extent, into differentiation. This correlates with the control of cyclin D1 transcription and of the expression of the p27/Kip1 protein. Interestingly, this functional aspect is not only associated with silencing of the Notch pathway but also appears to be independent of proneural function. Consistently, GATA2 also controls the proliferation capacity of mouse embryonic neuroepithelial cells in culture. Indeed, Gata2 inactivation enhances the proliferation rate in these cells. By contrast, GATA2 overexpression is sufficient to force such cells and neuroblastoma cells to stop dividing but not to drive either type of cell into differentiation. Furthermore, a non-cell autonomous effect of Gata2 expression was observed in vivo as well as in vitro. Hence, our data have provided evidence for the ability of Gata2 to inhibit the proliferation of neural progenitors, and they further suggest that, in this regard, Gata2 can operate independently of neuronal differentiation. -
Stoichiometric and Temporal Requirements of Oct4, Sox2, Klf4, and C-Myc Expression for Efficient Human Ipsc Induction and Differentiation
Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation Eirini P. Papapetroua,b, Mark J. Tomishimac,d, Stuart M. Chambersc, Yvonne Micae, Evan Reeda,b, Jayanthi Menona,f, Viviane Tabara,f, Qianxing Mog, Lorenz Studera,c, and Michel Sadelaina,b,1 aCenter for Cell Engineering, bMolecular Pharmacology and Chemistry and cDevelopmental Biology Programs, dSKI Stem Cell Research Facility, eGerstner Sloan-Kettering Graduate School, and Departments of fNeurosurgery and gEpidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065 Communicated by Mark Ptashne, Memorial Sloan–Kettering Cancer Center, New York, NY, May 1, 2009 (received for review April 8, 2009) Human-induced pluripotent stem cells (hiPSCs) are generated from purposes remains controversial (20). Furthermore, the significance somatic cells by ectopic expression of the 4 reprogramming factors of vector silencing for reprogramming and its impact on differen- (RFs) Oct-4, Sox2, Klf4, and c-Myc. To better define the stoichiometric tiation is unclear. Although it has been proposed that silencing of requirements and dynamic expression patterns required for success- factor expression is required for successful reprogramming and ful hiPSC induction, we generated 4 bicistronic lentiviral vectors multilineage differentiation (3, 21, 22), it remains unclear whether encoding the 4 RFs co-expressed with discernable fluorescent pro- vector silencing constitutes a requirement or an epiphenomenon of teins. Using this system, we define the optimal stoichiometry of RF the reprogramming process. expression to be highly sensitive to Oct4 dosage, and we demonstrate Here we present a vector system for iPSC induction that allows the impact that variations in the relative ratios of RF expression exert for simultaneous real-time tracking of expression of the 4 individual on the efficiency of hiPSC induction. -
SUPPLEMENTARY MATERIAL Bone Morphogenetic Protein 4 Promotes
www.intjdevbiol.com doi: 10.1387/ijdb.160040mk SUPPLEMENTARY MATERIAL corresponding to: Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells SUMIYO MIMURA, MIKA SUGA, KAORI OKADA, MASAKI KINEHARA, HIROKI NIKAWA and MIHO K. FURUE* *Address correspondence to: Miho Kusuda Furue. Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. Tel: 81-72-641-9819. Fax: 81-72-641-9812. E-mail: [email protected] Full text for this paper is available at: http://dx.doi.org/10.1387/ijdb.160040mk TABLE S1 PRIMER LIST FOR QRT-PCR Gene forward reverse AP2α AATTTCTCAACCGACAACATT ATCTGTTTTGTAGCCAGGAGC CDX2 CTGGAGCTGGAGAAGGAGTTTC ATTTTAACCTGCCTCTCAGAGAGC DLX1 AGTTTGCAGTTGCAGGCTTT CCCTGCTTCATCAGCTTCTT FOXD3 CAGCGGTTCGGCGGGAGG TGAGTGAGAGGTTGTGGCGGATG GAPDH CAAAGTTGTCATGGATGACC CCATGGAGAAGGCTGGGG MSX1 GGATCAGACTTCGGAGAGTGAACT GCCTTCCCTTTAACCCTCACA NANOG TGAACCTCAGCTACAAACAG TGGTGGTAGGAAGAGTAAAG OCT4 GACAGGGGGAGGGGAGGAGCTAGG CTTCCCTCCAACCAGTTGCCCCAAA PAX3 TTGCAATGGCCTCTCAC AGGGGAGAGCGCGTAATC PAX6 GTCCATCTTTGCTTGGGAAA TAGCCAGGTTGCGAAGAACT p75 TCATCCCTGTCTATTGCTCCA TGTTCTGCTTGCAGCTGTTC SOX9 AATGGAGCAGCGAAATCAAC CAGAGAGATTTAGCACACTGATC SOX10 GACCAGTACCCGCACCTG CGCTTGTCACTTTCGTTCAG Suppl. Fig. S1. Comparison of the gene expression profiles of the ES cells and the cells induced by NC and NC-B condition. Scatter plots compares the normalized expression of every gene on the array (refer to Table S3). The central line -
Long Noncoding RNA Lncpgcr Mediated by TCF7L2 Regulates Primordial Germ Cell Formation in Chickens
animals Article Long Noncoding RNA LncPGCR Mediated by TCF7L2 Regulates Primordial Germ Cell Formation in Chickens Jingyi Jiang 1, Chen Chen 1, Shaoze Cheng 1, Xia Yuan 1, Jing Jin 1, Chen Zhang 1, Xiaolin Sun 1 , Jiuzhou Song 2 , Qisheng Zuo 1, Yani Zhang 1, Guohong Chen 1 and Bichun Li 1,* 1 Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, Jiangsu, China; [email protected] (J.J.); [email protected] (C.C.); [email protected] (S.C.); [email protected] (X.Y.); [email protected] (J.J.); [email protected] (C.Z.); [email protected] (X.S.); [email protected] (Q.Z.); [email protected] (Y.Z.); [email protected] (G.C.) 2 Animal & Avian Sciences, University of Maryland, College Park, MD 20741, USA; [email protected] * Correspondence: [email protected] Simple Summary: The potential of primordial germ cells (PGCs) for multidirectional differentiation, together with their unique regeneration ability, makes them one of the most promising seed cells in clinical medicine and tissue engineering research. However, not enough PGCs can be obtained to meet the demand, which limits their application. We defined a novel long noncoding RNA (lncRNA) mediated by epigenetics, which could activate the miR-6577-5p/Btrc pathway to promote the formation of PGCs. The technical system we have established is a useful tool to obtain sufficient PGCs for scientific research. Our study offers great theoretical and practical value in the production of transgenic animals or genomic imprinting in poultry. -
NIH Public Access Author Manuscript Curr Opin Immunol
NIH Public Access Author Manuscript Curr Opin Immunol. Author manuscript; available in PMC 2012 April 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Curr Opin Immunol. 2011 April ; 23(2): 198±206. doi:10.1016/j.coi.2010.11.007. Aire and T cell Development Mark S. Andersona,* and Maureen A. Sub,* a Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA b Inflammatory Diseases Institute and Department of Pediatrics, University of North Carolina, Chapel Hill, Chapel Hill, NC Abstract In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self- antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a critical role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified. -
Crosstalk Between SOX2 and TGF-Β Signaling Regulates EGFR-TKI Tolerance and Lung Cancer Dissemination
Author Manuscript Published OnlineFirst on August 19, 2020; DOI: 10.1158/0008-5472.CAN-19-3228 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Crosstalk between SOX2 and TGF-β signaling regulates EGFR-TKI tolerance and lung cancer dissemination Ming-Han Kuo1,10, An-Chun Lee1,10, Shih-Hsin Hsiao2,10, Sey-En Lin3,4, Yu-Fan Chiu1, Li-Hao Yang1, Chia-Cherng Yu5, Shih-Hwa Chiou6,7, Hsien-Neng Huang8, Jen-Chung Ko9*, Yu-Ting Chou1* 1Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; 2Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; 3Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan; 4Department of Pathology, Taipei Municipal Wan Fang Hospital, Taipei, Taiwan; 5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; 6Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; 7Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; 8Department of pathology, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan; 9Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan;10Co-first authors *Corresponding authors Jen-Chung Ko, National Taiwan University Hospital, Hsin-Chu Branch, No. 25, Lane 442, Sec. 1, Jingguo Rd., Hsinchu 30013, Taiwan. E-mail: [email protected] Yu-Ting Chou, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Rd., Hsinchu 30013, Taiwan. E-mail: [email protected] Running title: Interplay of SOX2 and TGF- on EGFR–TKI tolerance Conflicts of interest The authors disclose no potential conflicts of interest. This work was supported by National Tsing Hua University and Ministry of Science and Technology, Executive Yuan, Taiwan. -
Construction of a Cerna Network Combining Transcription Factors in Eutopic Endometrial Tissue of Tubal Factor Infertility and Endometriosis-Related Infertility
Construction of a ceRNA network combining transcription factors in eutopic endometrial tissue of tubal factor infertility and endometriosis-related infertility Junzui Li ( [email protected] ) Xiamen University https://orcid.org/0000-0002-6640-8215 Lulu Ren Xiamen University Medical College Cui Yang Xiamen University Medical College Rongfeng Wu Xiamen University Medical College Zhixiong Huang Xiamen University School of Life Sciences Qionghua Chen Xiamen University Medical College Research article Keywords: TFI, endometriosis-related infertility, DEGs, ceRNA network, TFs Posted Date: December 19th, 2019 DOI: https://doi.org/10.21203/rs.2.19312/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/27 Abstract Purpose Although tubal factor infertility (TFI) and endometriosis-related infertility all can result in female infertility, the pathogenesis of TFI and endometriosis-related infertility were different. The pathophysiologic mechanisms of TFI and endometriosis-related infertility have not been investigated thoroughly. Thus, the aim of the study is to identify the potential crucial genes, pathways, transcription factors (TFs) and long non-coding RNAs (lncRNAs) associated with TFI and endometriosis-related infertility, and further analyze the molecular mechanism implicated in genes. Methods 3 patients with TFI and 3 patients with endometriosis-related infertility were recruited, and microarray hybridization of the eutopic endometrial tissue during the window of implantation (WOI) was performed to examine the expression of mRNAs and lncRNAs. First, differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) were screened out based on P < 0.05 and fold change (FC) ≧ 2. Second, gene ontology, pathway and TFs enrichment analyses and PPI network construction of DEGs were performed. -
Pancreas-Specific Deletion of Mouse Gata4 and Gata6 Causes Pancreatic Agenesis
Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis Shouhong Xuan, … , Raymond J. Macdonald, Lori Sussel J Clin Invest. 2012;122(10):3516-3528. https://doi.org/10.1172/JCI63352. Research Article Pancreatic agenesis is a human disorder caused by defects in pancreas development. To date, only a few genes have been linked to pancreatic agenesis in humans, with mutations in pancreatic and duodenal homeobox 1 (PDX1) and pancreas-specific transcription factor 1a (PTF1A) reported in only 5 families with described cases. Recently, mutations in GATA6 have been identified in a large percentage of human cases, and aG ATA4 mutant allele has been implicated in a single case. In the mouse, Gata4 and Gata6 are expressed in several endoderm-derived tissues, including the pancreas. To analyze the functions of GATA4 and/or GATA6 during mouse pancreatic development, we generated pancreas- specific deletions of Gata4 and Gata6. Surprisingly, loss of either Gata4 or Gata6 in the pancreas resulted in only mild pancreatic defects, which resolved postnatally. However, simultaneous deletion of both Gata4 and Gata6 in the pancreas caused severe pancreatic agenesis due to disruption of pancreatic progenitor cell proliferation, defects in branching morphogenesis, and a subsequent failure to induce the differentiation of progenitor cells expressing carboxypeptidase A1 (CPA1) and neurogenin 3 (NEUROG3). These studies address the conserved and nonconserved mechanisms underlying GATA4 and GATA6 function during pancreas development and provide a new mouse model to characterize the underlying developmental defects associated with pancreatic agenesis. Find the latest version: https://jci.me/63352/pdf Research article Related Commentary, page 3469 Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis Shouhong Xuan,1 Matthew J. -
O-Glcnac Modification of Oncogenic Transcription Factor Sox2 Promotes Protein Stability and Regulates Self-Renewal in Pancreatic Cancer
bioRxiv preprint doi: https://doi.org/10.1101/345223; this version posted June 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. O-GlcNAc modification of oncogenic transcription factor Sox2 promotes protein stability and regulates self-renewal in pancreatic cancer Nikita S Sharma1, Vineet K Gupta1, Patricia Dauer2, Kousik Kesh1, Roey Hadad1, Bhuwan Giri1, Anjali Chandra5, Vikas Dudeja1,4, Chad Slawson3, Santanu Banerjee1,4, Selwyn M Vickers6, Ashok Saluja1, 4 and Sulagna Banerjee1, 4* 1Department of Surgery, University of Miami, Miami, FL. 2Department of Pharmacology, University of Minnesota, Minneapolis Minnesota. 3University of Kansas Medical Center, Kansas City, KS. 4Sylvester Comprehensive Cancer Center, Miami, FL. 5 Department of Psychology, Harvard University. 6 School of Medicine Dean’s Office, University of Alabama at Birmingham. * Corresponding Author Address of Correspondence: 1550 NW 10th Ave Papanicolau Building, Suite 109B Miami, FL 33136 [email protected] (305)-243-8242 Running Title: O-GlcNAc modified Sox2 mediates self-renewal in PDAC Keywords: OGT, O-GlcNAc, Sox2, Pancreatic cancer, metabolism, self-renewal Financial Support This study was funded by NIH grants R01-CA170946 and R01-CA124723 (to AKS); NIH grant R01-CA184274 (to SB); Katherine and Robert Goodale foundation support (to AKS), Minneamrita Therapeutics LLC (to AKS). The authors would also like to acknowledge Oncogenomics Core at the Sylvester Cancer Center, University of Miami for their help with the RNA seq transcriptomics study. bioRxiv preprint doi: https://doi.org/10.1101/345223; this version posted June 12, 2018.