Gene Regulation in Eukaryotes Gene Regulation in Eukaryotes

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Regulation of Gene Expression Results in differential gene expression, leading to cell specialization Gene Expression Review • Inherited information flows from DNA to RNA to protein through the processes of transcription and translation Gene Expression Regulation • Gene expression can be regulated: – Before transcription – After transcription – After translation But first we must expose the gene by unpacking the DNA….. Histone Acetylation • Addition of acetyl groups (-COCH3) to histones – opens up chromatin (“on”) • Promotes transcription of specific genes DNA Methylation • Addition of methyl groups to DNA • Methylated DNA is not expressed (gene “off”) • Inactive genes are heavily methylated • Remove methyl groups – genes are activated MECP2 Acetylation and Methylation Epigenetics • External or environmental factors that modify the activation of certain genes (do not change the DNA sequence) • Epigenetic factors affect histone modification (through acetylation) and DNA methylation Exposed Gene Gene Structure Regulatory Sequences and Regulatory Genes • DNA regulatory sequences, regulatory genes, and small regulatory RNAs are involved in controlling gene expression 1. Regulatory sequences: stretches of DNA that interact with regulatory proteins to control transcription 2. Regulatory genes: a sequence of DNA encoding a regulatory protein or RNA Regulatory Sequence • Promoters, terminators and enhancers are all examples of regulatory sequences “Switch” • Regulatory sequences interact with regulatory proteins (coded for by regulatory genes) to act like a molecular “switch” turning genes on and off Regulatory Sequence: Enhancers • A short region of DNA upstream from a gene that activates transcription of a gene • Part of the molecular “switch” Enhancers Regulatory Genes • A sequence of DNA encoding a regulatory protein or RNA • MicroRNAs (miRNAs) are produced by regulatory genes Gene Regulation in Eukaryotes Gene Regulation in Eukaryotes • More complex that prokaryotic gene regulation because eukaryotic genes are controlled individually • Involves regulatory genes, regulatory sequences and transcription factors that all work together Gene Regulation in Eukaryotes • Transcription factors bind to specific DNA sequences and/or other regulatory proteins • Determine how much of a gene product will be produced 1. Activators: increase gene expression by promoting transcription (ex. MyoD) 2. Repressors: decrease gene expression by inhibiting transcription (ex. p21 protein) Activators Repressors Gene Regulation In Prokaryotes Prokaryotic Gene Regulation • Both positive and negative control mechanisms regulate gene expression in prokaryotes (bacteria) • Operon: cluster of genes under the control of a single promoter (less complex gene regulation) • Examples: – Lac operon (inducible operon) – Trp operon (repressible operon) Operon: Basic Structure Lac Operon • An inducible operon because it is usually turned OFF but can be stimulated (induced) • The sugar allolactose acts as the inducible molecule (inducer) Trp Operon • A repressible operon because it is usually turned ON but can be inhibited (repressed) • Tryptophan acts as the repressor molecule Negative and Positive Control • Negative control: regulatory proteins inhibit gene expression by blocking transcription of the gene • Positive control: regulatory proteins stimulate gene expression by promoting transcription of the gene • Both the lac operon and the trp operon have positive and negative control elements Negative Control Positive Control .

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Exploring the Structure of Long Non-Coding Rnas, J

IMF YJMBI-63988; No. of pages: 15; 4C: 3, 4, 7, 8, 10 1 2 Rise of the RNA Machines: Exploring the Structure of 3 Long Non-Coding RNAs 4 Irina V. Novikova, Scott P. Hennelly, Chang-Shung Tung and Karissa Y. Sanbonmatsu Q15 6 Los Alamos National Laboratory, Los Alamos, NM 87545, USA 7 Correspondence to Karissa Y. Sanbonmatsu: [email protected] 8 http://dx.doi.org/10.1016/j.jmb.2013.02.030 9 Edited by A. Pyle 1011 12 Abstract 13 Novel, profound and unexpected roles of long non-coding RNAs (lncRNAs) are emerging in critical aspects of 14 gene regulation. Thousands of lncRNAs have been recently discovered in a wide range of mammalian 15 systems, related to development, epigenetics, cancer, brain function and hereditary disease. The structural 16 biology of these lncRNAs presents a brave new RNA world, which may contain a diverse zoo of new 17 architectures and mechanisms. While structural studies of lncRNAs are in their infancy, we describe existing 18 structural data for lncRNAs, as well as crystallographic studies of other RNA machines and their implications 19 for lncRNAs. We also discuss the importance of dynamics in RNA machine mechanism. Determining 20 commonalities between lncRNA systems will help elucidate the evolution and mechanistic role of lncRNAs in 21 disease, creating a structural framework necessary to pursue lncRNA-based therapeutics. 22 © 2013 Published by Elsevier Ltd. 24 23 25 Introduction rather than the exception in the case of eukaryotic 50 organisms. 51 26 RNA is primarily known as an intermediary in gene LncRNAs are defined by the following: (i) lack of 52 11 27 expression between DNA and proteins.
Upstream Sequences Other Than AAUAAA Are Required for Efficient Messenger RNA 3’-End Formation in Plants

The Plant Cell, Vol. 2, 1261-1272, December 1990 O 1990 American Society of Plant Physiologists Upstream Sequences Other than AAUAAA Are Required for Efficient Messenger RNA 3’-End Formation in Plants Bradley D. Mogen, Margaret H. MacDonald, Robert Graybosch,’ and Arthur G. Hunt2 Plant Physiology/Biochemistry/MolecularBiology Program, Department of Agronomy, University of Kentucky, Lexington, Kentucky 40546-009 1 We have characterized the upstream nucleotide sequences involved in mRNA 3’-end formation in the 3‘ regions of the cauliflower mosaic virus (CaMV) 19S/35S transcription unit and a pea gene encoding ribulose-l,5-bisphosphate carboxylase small subunit (rbcs). Sequences between 57 bases and 181 bases upstream from the CaMV polyade- nylation site were required for efficient polyadenylation at this site. In addition, an AAUAAA sequence located 13 bases to 18 bases upstream from this site was also important for efficient mRNA 3’-end formation. An element located between 60 bases and 137 bases upstream from the poly(A) addition sites in a pea rbcS gene was needed for functioning of these sites. The CaMV -181/-57 and rbcS -137/-60 elements were different in location and sequence composition from upstream sequences needed for polyadenylation in mammalian genes, but resembled the signals that direct mRNA 3’-end formation in yeast. However, the role of the AAUAAA motif in 3’-end formation in the CaMV 3’ region was reminiscent of mRNA polyadenylation in animals. We suggest that multiple elements are involved in mRNA 3‘-end formation in plants, and that interactions of different components of the plant polyadenyl- ation apparatus with their respective sequence elements and with each other are needed for efficient mRNA 3‘-end formation.
Chapter 18 Regulation of Gene Expression Regulation of Gene Expression • Important for Cellular Control and Differentiation

Chapter 18 Regulation of Gene Expression Regulation of Gene Expression • Important for cellular control and differentiation. • Understanding “expression” is a “hot” area in Biology. General Mechanisms 1. Regulate Gene Expression 2. Regulate Protein Activity Operon Model • Jacob and Monod (1961) - Prokaryotic model of gene control. • Always on the National AP Biology exam! Operon Structure 1. Regulatory Gene 2. Operon Area a. Promoter b. Operator c. Structural Genes Gene Structures Regulatory Gene • Makes Repressor Protein which may bind to the operator. • Repressor protein blocks transcription. Promoter • Attachment sequence on the DNA for RNA polymerase to start transcription. Operator • The "Switch”, binding site for Repressor Protein. • If blocked, will not permit RNA polymerase to pass, preventing transcription. Structural Genes • Make the enzymes for the metabolic pathway. Lac Operon • For digesting Lactose. • Inducible Operon - only works (on) when the substrate (lactose) is present. If no Lactose • Repressor binds to operator. • Operon is "off”, no transcription, no enzymes made If Lactose is absent If Lactose is present • Repressor binds to Lactose instead of operator. • Operon is "on”, transcription occurs, enzymes are made. If Lactose is present Enzymes • Digest Lactose. • When enough Lactose is digested, the Repressor can bind to the operator and switch the Operon "off”. Net Result • The cell only makes the Lactose digestive enzymes when the substrate is present, saving time and energy. Animation • http://www.biostudio.com/d_%20Lac%20Ope ron.htm trp Operon • Makes/synthesizes Tryptophan. • Repressible Operon. – Predict how it is different from the inducible operon… If no Tryptophan • Repressor protein is inactive, Operon "on” Tryptophan made. • “Normal” state for the cell.
An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum Yang Eric Li1*, Sebastian Preissl2*, Xiaomeng Hou2, Ziyang Zhang1

bioRxiv preprint doi: https://doi.org/10.1101/2020.05.10.087585; this version posted May 11, 2020. 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 An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum 2 3 Yang Eric Li1*, Sebastian Preissl2*, Xiaomeng Hou2, Ziyang Zhang1, Kai Zhang1, Rongxin 4 Fang1, Yunjiang Qiu1, Olivier Poirion2, Bin Li1, Hanqing Liu3, Xinxin Wang2, Jee Yun Han2, 5 Jacinta Lucero4, Yiming Yan1, Samantha Kuan1, David Gorkin2, Michael Nunn3, Eran A. 6 Mukamel5, M. Margarita Behrens4, Joseph Ecker3,6 and Bing Ren1,2,7 7 8 *these authors contributed equally 9 10 1Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, CA 92093, USA 11 2Center for Epigenomics, Department of Cellular and Molecular Medicine, University of 12 California, San Diego, School of Medicine, La Jolla, CA, USA. 13 3Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, 14 92037, USA. 15 4Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, 16 CA 92037, USA 17 5Department of Cognitive Science, University of California, San Diego, La Jolla, CA 18 92037, USA. 19 6Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, 20 92037, USA. 21 7Institute of Genomic Medicine, Moores Cancer Center, University of California San 22 Diego, School of Medicine, La Jolla, CA, USA. 23 24 Correspondence: Bing Ren ([email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.05.10.087585; this version posted May 11, 2020.
POST-TRANSCRIPTIONAL REGULATION of AFP and Igm GENES

University of Kentucky UKnowledge University of Kentucky Doctoral Dissertations Graduate School 2011 POST-TRANSCRIPTIONAL REGULATION OF AFP AND IgM GENES Lilia M. Turcios University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Turcios, Lilia M., "POST-TRANSCRIPTIONAL REGULATION OF AFP AND IgM GENES" (2011). University of Kentucky Doctoral Dissertations. 210. https://uknowledge.uky.edu/gradschool_diss/210 This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION Lilia M. Turcios The Graduate School University of Kentucky 2011 POST-TRANSCRIPTIONAL REGULATION OF AFP AND IgM GENES ABSTRACT OF DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Lilia M. Turcios Director: Dr. Martha Peterson Lexington, KY 2011 Copyright © Lilia M. Turcios 2011 ABSTRACT OF DISSERTATION POST-TRANSCRIPTIONAL REGULATION OF AFP AND IgM GENES Gene expression can be regulated at multiple steps once transcription is initiated. I have studied two different gene models, the α-Fetoprotein (AFP) and the immunoglobulin heavy chain (IgM) genes, to better understand post-transcriptional gene regulation mechanisms. The AFP gene is highly expressed during fetal liver development and dramatically repressed after birth. There is a mouse strain-specific difference between adult levels of AFP, with BALB/cJ mice expressing 10 to 20-fold higher levels compared to other mouse strains.
Evolution of Genomic Expression

C H A P T E R 5 Evolution of Genomic Expression Bernardo Lemos, Christian R. Landry, Pierre Fontanillas, Susan P. Renn, Rob Kulathinal, Kyle M. Brown, and Daniel L. Hartl Introduction Genomic regulation is key to cellular differentiation, tissue morphogenesis, and development. Increasing evidence indicates that evolutionary diversity of phenotypes—from cellular to organismic—may also be, in large part, the result of variation in the regulation of genomic expression. In this chapter we explore the complexity of gene regulation from the perspective of single genes and whole genomes. The first part describes the major factors affecting gene expression levels, from rates of gene transcrip- tion—as mediated by promoter–enhancer interactions and chromatin mod- ifications—to rates of mRNA degradation. This description underscores the multiple levels at which genomic expression can be regulated as well as the complexity and variety of mechanisms used. We then briefly describe the major experimental and computational biology techniques for analyzing gene expression variation and its underlying causes. The final section reviews our understanding of the role of regulatory variation in evolution, including the molecular evolution and population genetics of noncoding DNA, as well as the inheritance and phenotypic evolution of levels of mRNA abundance. The Complex Regulation of Genomic Expression The regulation of gene expression is a complex and dynamic process. It is not a simple matter to turn a gene on and off, let alone precisely regulate its level of expression. Regulation can be accomplished through various mech- anisms at nearly every step of the process of gene expression. Furthermore, each mechanism may require a variety of elements, including DNA sequences, RNA molecules, and proteins, acting in combination to deter- 2 Chapter Five Evolution of Genomic Expression 3 mine the final amount, timing, and location of functional gene product.
In Response to DNA Damage and C&Sol

Oncogene (2009) 28, 3235–3245 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE C/EBPa expression is partially regulated by C/EBPb in response to DNA damage and C/EBPa-deficient fibroblasts display an impaired G1 checkpoint R Ranjan1, EA Thompson1, K Yoon2 and RC Smart1 1Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC, USA and 2National Cancer Center, Division of Common Cancers, Lung Cancer Branch, Goyang-si, Gyeonggi-do, South Korea We observed that CCAAT/enhancer-binding protein involved in homo- or hetero-dimerization (Ramji and (C/EBP)a is highly inducible in primary fibroblasts by Foka, 2002). The N-terminal region contains transcrip- DNA-damaging agents that induce strand breaks, alky- tion activation and regulatory domains that interact late and crosslink DNA as well as those that produce with basal transcription apparatus and transcription bulky DNA lesions. Fibroblasts deficient in C/EBPa co-activators. There are six members of the C/EBP family À/À (C/EBPa ) display an impaired G1 checkpoint as and C/EBPs have important functions in fundamental evidenced by an inappropriate entry into the S-phase in cellular processes, including proliferation, apoptosis, response to DNA damage, and these cells also display an differentiation, inflammation, senescence and energy enhanced G1/S transition in response to mitogens. The metabolism (Ramji and Foka, 2002; Johnson, 2005). induction of C/EBPa by DNA
Molecular Basis of the Function of Transcriptional Enhancers

cells Review Molecular Basis of the Function of Transcriptional Enhancers 1,2, 1, 1,3, Airat N. Ibragimov y, Oleg V. Bylino y and Yulii V. Shidlovskii * 1 Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia; [email protected] (A.N.I.); [email protected] (O.V.B.) 2 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia 3 I.M. Sechenov First Moscow State Medical University, 8, bldg. 2 Trubetskaya St., 119048 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-4991354096 These authors contributed equally to this study. y Received: 30 May 2020; Accepted: 3 July 2020; Published: 5 July 2020 Abstract: Transcriptional enhancers are major genomic elements that control gene activity in eukaryotes. Recent studies provided deeper insight into the temporal and spatial organization of transcription in the nucleus, the role of non-coding RNAs in the process, and the epigenetic control of gene expression. Thus, multiple molecular details of enhancer functioning were revealed. Here, we describe the recent data and models of molecular organization of enhancer-driven transcription. Keywords: enhancer; promoter; chromatin; transcriptional bursting; transcription factories; enhancer RNA; epigenetic marks 1. Introduction Gene transcription is precisely organized in time and space. The process requires the participation of hundreds of molecules, which form an extensive interaction network. Substantial progress was achieved recently in our understanding of the molecular processes that take place in the cell nucleus (e.g., see [1–9]).
RNA-Based Regulation of Genes of Tryptophan Synthesis and Degradation, in Bacteria

REVIEW RNA-based regulation of genes of tryptophan synthesis and degradation, in bacteria CHARLES YANOFSKY Department of Biological Sciences, Stanford University Stanford, California 94305, USA ABSTRACT We are now aware that RNA-based regulatory mechanisms are commonly used to control gene expression in many organisms. These mechanisms offer the opportunity to exploit relatively short, unique RNA sequences, in altering transcription, translation, and/or mRNA stability, in response to the presence of a small or large signal molecule. The ability of an RNA segment to fold and form alternative hairpin secondary structures—each dedicated to a different regulatory function—permits selection of specific sequences that can affect transcription and/or translation. In the present paper I will focus on our current understanding of the RNA-based regulatory mechanisms used by Escherichia coli and Bacillus subtilis in controlling expression of the tryptophan biosynthetic operon. The regulatory mechanisms they use for this purpose differ, suggesting that these organisms, or their ancestors, adopted different strategies during their evolution. I will also describe the RNA-based mechanism used by E. coli in regulating expression of its operon responsible for tryptophan degradation, the tryptophanase operon. Keywords: trp operon; trp suboperon; aro supraoperon; tna operon; transcription attenuation; T box regulation; tryptophan as a regulatory signal; tRNATrp as a regulatory signal; peptidyl-tRNA; ribosome mediated regulation INTRODUCTION A second regulatory lesson learned over the years is that information within mRNAs, or other RNAs, as well as small Studies over the past 50+ years have revealed that metabolites and other molecules—in addition to DNA and optimization of gene expression has been a major evolu- proteins—often provides specific regulatory signals, or tionary objective for most species.
The Nucleotide Sequence of the Gene for Human Protein C (DNA Sequence Analysis/Vitamin K-Dependent Proteins/Blood Coagulation) DONALD C

Proc. Natl. Acad. Sci. USA Vol. 82, pp. 4673-4677, July 1985 Biochemistry The nucleotide sequence of the gene for human protein C (DNA sequence analysis/vitamin K-dependent proteins/blood coagulation) DONALD C. FOSTER, SHINJI YOSHITAKE, AND EARL W. DAVIE Department of Biochemistry, University of Washington, Seattle, WA 98195 Contributed by Earl W. Davie, April 9, 1985 ABSTRACT A human genomic DNA library was screened MATERIALS AND METHODS for the gene for protein C by using a cDNA probe coding for the human protein. Three different overlapping A Charon 4A Screening of the Genomic Library. A human genomic phage were isolated that contain inserts for the gene for protein library in X Charon 4A phage (14) was screened for genomic C. The complete sequence of the gene was determined by the clones of human protein C by the plaque hybridization dideoxy method and shown to span about 11 kilobases ofDNA. procedure ofBenton and Davis as modified by Woo (15) using The coding and 3' noncoding portion of the gene consists of a cDNA for human protein C (9) as the hybridization probe. eight exons and seven introns. The eight exons code for a The cDNA started at amino acid 64 of human protein C and preproleader sequence of 42 amino acids, a light chain of 155 extended to the second polyadenylylation signal (9). It was amino acids, a connecting dipeptide of Lys-Arg, and a heavy radiolabeled by nick-translation to a specific activity of 8 X chain of 262 amino acids. The preproleader sequence and the 108 cpm/,ug with all four radioactive ([a-32P]dNTP) connecting dipeptide are removed during processing, resulting deoxynucleotides.
Chapter 3. the Beginnings of Genomic Biology – Molecular

Chapter 3. The Beginnings of Genomic Biology – Molecular Genetics Contents 3. The beginnings of Genomic Biology – molecular genetics 3.1. DNA is the Genetic Material 3.6.5. Translation initiation, elongation, and termnation 3.2. Watson & Crick – The structure of DNA 3.6.6. Protein Sorting in Eukaryotes 3.3. Chromosome structure 3.7. Regulation of Eukaryotic Gene Expression 3.3.1. Prokaryotic chromosome structure 3.7.1. Transcriptional Control 3.3.2. Eukaryotic chromosome structure 3.7.2. Pre-mRNA Processing Control 3.3.3. Heterochromatin & Euchromatin 3.4. DNA Replication 3.7.3. mRNA Transport from the Nucleus 3.4.1. DNA replication is semiconservative 3.7.4. Translational Control 3.4.2. DNA polymerases 3.7.5. Protein Processing Control 3.4.3. Initiation of replication 3.7.6. Degradation of mRNA Control 3.4.4. DNA replication is semidiscontinuous 3.7.7. Protein Degradation Control 3.4.5. DNA replication in Eukaryotes. 3.8. Signaling and Signal Transduction 3.4.6. Replicating ends of chromosomes 3.8.1. Types of Cellular Signals 3.5. Transcription 3.8.2. Signal Recognition – Sensing the Environment 3.5.1. Cellular RNAs are transcribed from DNA 3.8.3. Signal transduction – Responding to the Environment 3.5.2. RNA polymerases catalyze transcription 3.5.3. Transcription in Prokaryotes 3.5.4. Transcription in Prokaryotes - Polycistronic mRNAs are produced from operons 3.5.5. Beyond Operons – Modification of expression in Prokaryotes 3.5.6. Transcriptions in Eukaryotes 3.5.7. Processing primary transcripts into mature mRNA 3.6. Translation 3.6.1.
Bicyclomycin Sensitivity and Resistance Affect Rho Factor-Mediated Transcription Termination in the Tna Operon of Escherichia Coli

JOURNAL OF BACTERIOLOGY, Aug. 1995, p. 4451–4456 Vol. 177, No. 15 0021-9193/95/$04.0010 Copyright 1995, American Society for Microbiology Bicyclomycin Sensitivity and Resistance Affect Rho Factor-Mediated Transcription Termination in the tna Operon of Escherichia coli CHARLES YANOFSKY* AND VIRGINIA HORN Department of Biological Sciences, Stanford University, Stanford, California 94305-5020 Received 13 March 1995/Accepted 27 May 1995 The growth-inhibiting drug bicyclomycin, known to be an inhibitor of Rho factor activity in Escherichia coli, was shown to increase basal level expression of the tryptophanase (tna) operon and to allow growth of a tryptophan auxotroph on indole. The drug also relieved polarity in the trp operon and permitted growth of a trp double nonsense mutant on indole. Nine bicyclomycin-resistant mutants were isolated and partially characterized. Recombination data and genetic and biochemical complementation analyses suggest that ﬁve have mutations that affect rho, three have mutations that affect rpoB, and one has a mutation that affects a third locus, near rpoB. Individual mutants showed decreased, normal, or increased basal-level expression of the tna operon. All but one of the resistant mutants displayed greatly increased tna operon expression when grown in the presence of bicyclomycin. The tna operon of the wild-type drug-sensitive parent was also shown to be highly expressed during growth with noninhibitory concentrations of bicyclomycin. These ﬁndings demonstrate that resistance to this drug may be acquired by mutations at any one of three loci, two of which appear to be rho and rpoB. Zwiefka et al. (24) found that the antibiotic bicyclomycin segment and interacts with the transcribing RNA polymerase (bicozamycin), an inhibitor of the growth of several gram- molecule, causing it to terminate transcription (7, 9).