Global Reference Mapping and Dynamics of Human Transcription Factor Footprints
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Core Transcriptional Regulatory Circuitries in Cancer
Oncogene (2020) 39:6633–6646 https://doi.org/10.1038/s41388-020-01459-w REVIEW ARTICLE Core transcriptional regulatory circuitries in cancer 1 1,2,3 1 2 1,4,5 Ye Chen ● Liang Xu ● Ruby Yu-Tong Lin ● Markus Müschen ● H. Phillip Koeffler Received: 14 June 2020 / Revised: 30 August 2020 / Accepted: 4 September 2020 / Published online: 17 September 2020 © The Author(s) 2020. This article is published with open access Abstract Transcription factors (TFs) coordinate the on-and-off states of gene expression typically in a combinatorial fashion. Studies from embryonic stem cells and other cell types have revealed that a clique of self-regulated core TFs control cell identity and cell state. These core TFs form interconnected feed-forward transcriptional loops to establish and reinforce the cell-type- specific gene-expression program; the ensemble of core TFs and their regulatory loops constitutes core transcriptional regulatory circuitry (CRC). Here, we summarize recent progress in computational reconstitution and biologic exploration of CRCs across various human malignancies, and consolidate the strategy and methodology for CRC discovery. We also discuss the genetic basis and therapeutic vulnerability of CRC, and highlight new frontiers and future efforts for the study of CRC in cancer. Knowledge of CRC in cancer is fundamental to understanding cancer-specific transcriptional addiction, and should provide important insight to both pathobiology and therapeutics. 1234567890();,: 1234567890();,: Introduction genes. Till now, one critical goal in biology remains to understand the composition and hierarchy of transcriptional Transcriptional regulation is one of the fundamental mole- regulatory network in each specified cell type/lineage. -
DNA Footprinting with an Automated DNA Analyzer: Does the Shoe Fit?
DNA Footprinting with an automated DNA Analyzer: does the shoe fit? Michael Zianni Manager, Plant-Microbe Genomics Facility DNA Footprinting with an Applied Biosystems 3730 DNA Analyzer: does the shoe fit ……….yes! DNA Footprint Analysis DNA Fragment BSA 6FAM DNA Binding Protein 6FAM Endonuclease Digestion (DNase I) 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM Capillary Electrophoresis rfu rfu Size (bp) Size (bp) 6FAM HrpY DNA Fragment 6FAM BSA 6FAM HrpY DNA Fragment 6FAM BSA Endonuclease EndonucleaseDigestion (DNaseDigestion I) (DNase I) 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM 6FAM Capillary ElectrophoresisCapillary Electrophoresis rfu rfu rfu rfu Size (bp) Size (bp) Size (bp) Size (bp) Development of DNA Foot print Analysis Techniques and Goals of This Study First performed in 1977, and utilized radioactively labeled DNA, slab gels, and autoradiography In 1994, dyes and fluorescent gel imager were used instead of radioisotopes and autoradiography but the slab gel remained. In 2000, the slab gel and imager were replaced by an automated capillary electrophoresis instrument: 310 DNA Analyzer. In 2004, ........... Demonstrate the feasibility by reproducing a protection assay previously done with autoradiography and a slab gel Demonstrate that each peak could be accurately identified Apply this method to a previously uncharacterized protein DNA Footprint analysis with protein: Autoradiography vs Electropherogram DNA Footprint analysis without protein: Electropherogram vs Autoradiography Fluorescent Primer Design For use in: (1) the DNA sequencing reactions which act as a standard/ladder and (2) the PCR reaction to make the DNA probe Used routine DNA sequencing guidelines: 18 -25mer. Tm at 55 – 60C. about 50% GC. -
Locating Mammalian Transcription Factor Binding Sites: a Survey of Computational and Experimental Techniques
Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Review Locating mammalian transcription factor binding sites: A survey of computational and experimental techniques Laura Elnitski,1,4 Victor X. Jin,2 Peggy J. Farnham,2 and Steven J.M. Jones3 1Genomic Functional Analysis Section, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland 20878, USA; 2Genome and Biomedical Sciences Facility, University of California–Davis, Davis, California 95616-8645, USA; 3Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z-4E6 Fields such as genomics and systems biology are built on the synergism between computational and experimental techniques. This type of synergism is especially important in accomplishing goals like identifying all functional transcription factor binding sites in vertebrate genomes. Precise detection of these elements is a prerequisite to deciphering the complex regulatory networks that direct tissue specific and lineage specific patterns of gene expression. This review summarizes approaches for in silico, in vitro, and in vivo identification of transcription factor binding sites. A variety of techniques useful for localized- and high-throughput analyses are discussed here, with emphasis on aspects of data generation and verification. [Supplemental material is available online at www.genome.org.] One documented goal of the National Human Genome Research and other regulatory elements is mediated by DNA/protein in- Institute (NHGRI) is the identification of all functional noncod- teractions. Thus, one major step in the characterization of the ing elements in the human genome (ENCODE Project Consor- functional elements of the human genome is the identification tium 2004). -
Glioblastoma Stem Cells Induce Quiescence in Surrounding Neural Stem Cells Via Notch Signalling
bioRxiv preprint doi: https://doi.org/10.1101/856062; this version posted November 29, 2019. 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. Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling. Katerina Lawlor1, Maria Angeles Marques-Torrejon2, Gopuraja Dharmalingham3, Yasmine El-Azhar1, Michael D. Schneider1, Steven M. Pollard2§ and Tristan A. Rodríguez1§ 1National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. 2 MRC Centre for Regenerative Medicine & Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK. 3MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Imperial College London, UK §Authors for correspondence: [email protected] and [email protected] Running title: Glioblastoma stem cell competition Keyword: Neural stem cells, quiescence, glioblastoma, Notch, cell competition 1 bioRxiv preprint doi: https://doi.org/10.1101/856062; this version posted November 29, 2019. 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. 1 Abstract 2 There is increasing evidence suggesting that adult neural stem cells (NSCs) are a cell of 3 origin of glioblastoma, the most aggressive form of malignant glioma. The earliest stages of 4 hyperplasia are not easy to explore, but likely involve a cross-talk between normal and 5 transformed NSCs. How normal cells respond to this cross-talk and if they expand or are 6 outcompeted is poorly understood. -
Supplemental Materials ZNF281 Enhances Cardiac Reprogramming
Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7 -
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 -
What Would You Do If You Could Sequence Everything?
PERspECTIVE What would you do if you could sequence everything? Avak Kahvejian1, John Quackenbush2 & John F Thompson1 It could be argued that the greatest transformative aspect ing technologies, be leveraged with insightful approaches to biology and of the Human Genome Project has been not the sequencing medicine to maximize the benefits to all? DNA sequence is no longer just of the genome itself, but the resultant development of new an end in itself, but it is rapidly becoming the digital substrate replac- technologies. A host of new approaches has fundamentally ing analog chip-based hybridization signals; it is the barcode tracking of changed the way we approach problems in basic and enormous numbers of samples; and it is the readout indicating a host of translational research. Now, a new generation of high-throughput chemical modifications and intermolecular interactions. Sequence data sequencing technologies promises to again transform the allow one to count mRNAs or other species of nucleic acids precisely, to scientific enterprise, potentially supplanting array-based determine sharp boundaries for interactions with proteins or positions technologies and opening up many new possibilities. By allowing of translocations and to identify novel variants and splice sites, all in one http://www.nature.com/naturebiotechnology DNA/RNA to be assayed more rapidly than previously possible, experiment with digital accuracy. these next-generation platforms promise a deeper understanding The brief history of molecular biology and genomic technologies has of genome regulation and biology. Significantly enhancing been marked by the introduction of new technologies, their rapid uptake sequencing throughput will allow us to follow the evolution and then a steady state or slow decline in use as newer techniques are of viral and bacterial resistance in real time, to uncover the developed that supersede them. -
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 -
Alveolar Rhabdomyosarcoma-Associated Proteins PAX3/FOXO1A and PAX7/FOXO1A Suppress the Transcriptional Activity of Myod-Target Genes in Muscle Stem Cells
Oncogene (2013) 32, 651 --662 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc ORIGINAL ARTICLE Alveolar rhabdomyosarcoma-associated proteins PAX3/FOXO1A and PAX7/FOXO1A suppress the transcriptional activity of MyoD-target genes in muscle stem cells F Calhabeu1, S Hayashi2, JE Morgan3, F Relaix2 and PS Zammit1 Rhabdomyosarcoma (RMS) is the commonest soft-tissue sarcoma in childhood and is characterized by expression of myogenic proteins, including the transcription factors MyoD and myogenin. There are two main subgroups, embryonal RMS and alveolar RMS (ARMS). Most ARMS are associated with chromosomal translocations that have breakpoints in introns of either PAX3 or PAX7, and FOXO1A. These translocations create chimeric transcription factors termed PAX3/FOXO1A and PAX7/FOXO1A respectively. Upon ectopic PAX3/FOXO1A expression, together with other genetic manipulation in mice, both differentiating myoblasts and satellite cells (the resident stem cells of postnatal muscle) can give rise to tumours with ARMS characteristics. As PAX3 and PAX7 are part of transcriptional networks that regulate muscle stem cell function in utero and during early postnatal life, PAX3/FOXO1A and PAX7/FOXO1A may subvert normal PAX3 and PAX7 functions. Here we examined how PAX3/FOXO1A and PAX7/FOXO1A affect myogenesis in satellite cells. PAX3/FOXO1A or PAX7/FOXO1A inhibited myogenin expression and prevented terminal differentiation in murine satellite cells: the same effect as dominant-negative (DN) Pax3 or Pax7 constructs. The transcription of MyoD-target genes myogenin and muscle creatine kinase were suppressed by PAX3/FOXO1A or PAX7/ FOXO1A in C2C12 myogenic cells again as seen with Pax3/7DN. PAX3/FOXO1A or PAX7/FOXO1A did not inhibit the transcriptional activity of MyoD by perturbing MyoD expression, localization, phosphorylation or interaction with E-proteins. -
The Camp Signaling System Regulates Lhβ Gene Expression: Roles of Early
291 The cAMP signaling system regulates LH gene expression: roles of early growth response protein-1, SP1 and steroidogenic factor-1 C D Horton and L M Halvorson Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032, USA (Requests for offprints should be addressed to L M Halvorson; Email: [email protected]) Abstract Expression of the gonadotropin genes has been shown to be modulated by pharmacological or physiological activators of both the protein kinase C (PKC) and the cAMP second messenger signaling pathways. Over the past few years, a substantial amount of progress has been made in the identification and characterization of the transcription factors and cognate cis-elements which mediate the PKC response in the LH -subunit (LH) gene. In contrast, little is known regarding the molecular mechanisms which mediate cAMP-mediated regulation of this gene. Using pituitary cell lines, we now demonstrate that rat LH gene promoter activity is stimulated following activation of the cAMP system by the adenylate cyclase activating agent, forskolin, or by the peptide, pituitary adenylate cyclase-activating peptide. The forskolin response was eliminated with mutation of a previously identified 3′ cis-acting element for the early growth response protein-1 (Egr-1) when evaluated in the context of region −207/+5 of the LH gene. Activation of the cAMP system increased Egr-1 gene promoter activity, Egr-1 protein levels and Egr-1 binding to the LH gene promoter, supporting the role of this transcription factor in mediating the cAMP response. Analysis of a longer LH promoter construct (−797/+5) revealed additional contribution by upstream Sp1 DNA-regulatory regions. -
Otx1 and Otx2 in Inner Ear Development 2337 by BMP4 Expression (Lc in Fig
Development 126, 2335-2343 (1999) 2335 Printed in Great Britain © The Company of Biologists Limited 1999 DEV1416 Otx1 and Otx2 activities are required for the normal development of the mouse inner ear Hakim Morsli1, Francesca Tuorto2, Daniel Choo1,*, Maria Pia Postiglione2, Antonio Simeone2 and Doris K. Wu1,‡ 1National Institute on Deafness and Other Communication Disorders, 5 Research Ct., Rockville, MD 20850, USA 2International Institute of Genetics and Biophysics, CNR, Via G. Marconi, 12, 80125 Naples, Italy *Present address: Children’s Hospital Medical Center of Cincinnati, Department of Otolaryngology, 3333 Burnet Ave., Cincinnati, OH 45229, USA ‡Author for correspondence (e-mail: [email protected]) Accepted 12 March; published on WWW 4 May 1999 SUMMARY The Otx1 and Otx2 genes are two murine orthologues of variable in Otx1−/− mice and were much more severe the Orthodenticle (Otd) gene in Drosophila. In the in an Otx1−/−;Otx2+/− background. Histological and in developing mouse embryo, both Otx genes are expressed situ hybridization experiments of both Otx1−/− and in the rostral head region and in certain sense organs such Otx1−/−;Otx2+/− mutants revealed that the lateral crista as the inner ear. Previous studies have shown that mice was absent. In addition, the maculae of the utricle and lacking Otx1 display abnormal patterning of the brain, saccule were partially fused. In mutant mice in which whereas embryos lacking Otx2 develop without heads. In both copies of the Otx1 gene were replaced with a human this study, we examined, at different developmental Otx2 cDNA (hOtx21/ hOtx21), most of the defects stages, the inner ears of mice lacking both Otx1 and Otx2 associated with Otx1−/− mutants were rescued. -
Microarray-Based Analysis of Genes, Transcription Factors, and Epigenetic Modifications in Lung Cancer Exposed to Nitric Oxide
CANCER GENOMICS & PROTEOMICS 17 : 401-415 (2020) doi:10.21873/cgp.20199 Microarray-based Analysis of Genes, Transcription Factors, and Epigenetic Modifications in Lung Cancer Exposed to Nitric Oxide ARNATCHAI MAIUTHED 1, ORNJIRA PRAKHONGCHEEP 2,3 and PITHI CHANVORACHOTE 2,3 1Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 2Cell-based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; 3Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand Abstract. Background/Aim: Nitric oxide (NO) is recognized NO exposure of lung cancer cells resulted in a change in as an important biological mediator that exerts several transcription factors (TFs) and epigenetic modifications human physiological functions. As its nature is an aqueous (histone modification and miRNA). Interestingly, NO soluble gas that can diffuse through cells and tissues, NO treatment was shown to potentiate cancer stem cell-related can affect cell signaling, the phenotype of cancer and modify genes and transcription factors Oct4, Klf4, and Myc. surrounding cells. The variety of effects of NO on cancer cell Conclusion: Through this comprehensive approach, the biology has convinced researchers to determine the defined present study illustrated the scheme of how NO affects mechanisms of these effects and how to control this mediator molecular events in lung cancer cells. for a better understanding as well as for therapeutic gain. Materials and Methods: We used bioinformatics and Lung cancer is one of the leading causes of cancer-related pharmacological experiments to elucidate the potential deaths worldwide (1, 2). Since the aggressive phenotypes regulation and underlying mechanisms of NO in non-small and treatment failures have been frequently observed in lung a lung cancer cell model.