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The Role of the Ubiquitously Expressed Transcription Factor Sp1 in Tissue-specific Transcriptional Regulation and in Disease O'Connor, Leigh; Gilmour, Jane; Bonifer, Constanze License: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): O'Connor, L, Gilmour, J & Bonifer, C 2016, 'The Role of the Ubiquitously Expressed Transcription Factor Sp1 in Tissue-specific Transcriptional Regulation and in Disease', Yale Journal of Biology and Medicine, vol. 89, no. 4, pp. 513-525. Link to publication on Research at Birmingham portal Publisher Rights Statement: Copyright ©2016, Yale Journal of Biology and Medicine. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License, which permits for noncommercial use, distribution, and reproduction in any digital medium, provided the original work is properly cited and is not altered in any way. General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. 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Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive. If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access to the work immediately and investigate. Download date: 01. Feb. 2019 YALE JOURNAL OF BIOLOGY AND MEDICINE 89 (2016), pp.513-525. RevIeW The Role of the Ubiquitously Expressed Transcription Factor Sp1 in Tissue-specific Transcriptional Regulation and in Disease Leigh O’Connor *, Jane Gilmour, Constanze Bonifer * Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, UK Sp1 belongs to the 26 member strong Sp/KLF family of transcription factors. It is a paradigm for a ubiqui - tously expressed transcription factor and is involved in regulating the expression of genes associated with a wide range of cellular processes in mammalian cells. Sp1 can interact with a range of proteins, including other transcription factors, members of the transcription initiation complex and epigenetic regulators, en - abling tight regulation of its target genes. In this review, we discuss the mechanisms involved in Sp1-medi - ated transcriptional regulation, as well as how a ubiquitous transcription factor can be involved in establishing a tissue-specific pattern of gene expression and mechanisms by which its activity may be regu - lated. We also consider the role of Sp1 in human diseases, such as cancer. INTRODUCTION gene for transcription or, in the case of repressors, block - Gene expression needs to be tightly regulated as the ing it. specific pattern of gene activation or repression is deci - Transcription factors interact in a combinatorial sive for establishing fates. The gene expression program fashion to uniquely regulate genes and, in response to dif - of a cell is controlled by the activities and the interac - ferent stimuli, regulate tissue-specific and developmen - tions of the epigenetic regulatory machinery and se - tal stage-specific gene expression. Many transcription quence-specific transcription factors. The epigenetic factors are expressed in a tissue-specific manner and reg - machinery consists of enzymes that post-translationally ulate the specialized functions of a particular cell; there - modify histone proteins, such as histone acetyltrans - fore elimination of these factors can result in a block in ferases (HATs †), histone deacetylases (HDACs), histone development/differentiation. For example, SCL/TAL1 is kinases and methyltransferases, as well as ATP-depen - a crucial transcription factor in the hematopoietic system dent chromatin remodeling complexes [1]. These factors and the deletion of its gene in mice results in a failure to regulate gene expression by altering the conformation of generate hematopoietic precursors and embryonic death DNA and allowing access to key regulatory elements of [2]. Other transcription factors are ubiquitously expressed transcription. Transcription factors bind to specific reg - and are generally involved in the expression of ubiqui - ulatory sequences in the DNA and regulate transcription tously expressed “housekeeping” genes in all cell types. of the associated gene by promoting recruitment of the However, they can also interact with tissue-specific pro - transcription initiation machinery. Additionally, tran - teins or be post-translationally modified in a tissue-spe - scription factors are capable of directing histone modi - cific manner to elicit a particular pattern of gene fying enzymes and chromatin remodeling complexes to expression. Nuclear Factor I (NFI) family members are specific sites, such as gene promoters, thus preparing the ubiquitously expressed and are involved in the regulation of constitutive genes and those that are controlled by hor - *To whom all correspondence should be addressed: Leigh O’Connor, Tel: +44 121 4158683, email: [email protected]; Con - stanze Bonifer, Tel: +44 121 4148881, email: [email protected]. †Abbreviations: AML, acute myeloid leukemia; BTD, Buttonhead domain; DNMT, DNA methyltransferase; EMSA, electrophoretic mobility shift assay; EMT, epithelial-mesenchymal transition; ER, estrogen receptor; ESC, embryonic stem cell; HAT, histone acetyl - transferase; HCC, Hepatocellular carcinoma; HDAC, histone deacetylase; Htt, Huntingtin; KLF, Krüppel-like factor; MS, multiple sclerosis; NFI, Nuclear Factor I; Sp, Specificity protein; TAF, TBP-associated factors; TBP, TATA-binding protein; TK, Thymidine Ki - nase. Keywords: Sp1 transcription factor, gene regulation, tissue specificity, human disease, epigenetics Copyright © 2016 513 514 O’Connor et al.: Transcriptional regulation by Sp1 monal, nutritional, and developmental signaling [3]. How - Specificity protein 1 [16,17]. When whole cell extracts ever, the knockout of individual NFI members results in were prepared from HeLa cells to study the factors re - tissue-specific defects. For example, NFI-A knockout quired for transcription initiation in vitro , Dynan and Tjian mice have a defect in brain development (formation of the identified that one of these factors, Sp1, showed sequence corpus callosum) but few other anatomical problems [4]. specificity and was able to bind to the Sv40 early pro - This suggests that the four NFI family members have moter and activate transcription of the gene [18]. overlapping roles and can compensate for the lack of NFI- Sp1 is the founding member of the Specificity pro - A activity, but there are distinct functions in specific tis - tein/Krüppel-like factor (Sp/KLF) family of transcription sues, revealed by the defects, indicating ubiquitous factors, which currently has a total of 26 members [19]. transcription factors have important roles in development The family is characterized by the highly conserved DNA and tissue-specific gene expression. Conversely, knock - binding domain (sequence identity > 65 percent) near to out of the gene encoding OCT1, another ubiquitously ex - the C-terminus of all members, which recognize GC (con - pressed transcription factor, leads to developmental arrest sensus sequence: GGGGCGGGG), as well as GT/CACC at a very early embryonic stage [5], suggesting widespread (GGTGTGGGG) boxes [16,20-22]. The DNA binding do - roles. Although OCT1 is important in the expression of main is made up of three adjacent Cys2His2-type zinc fin - housekeeping genes, such as H2B [6], it also activates tis - gers consisting of exactly 81 amino acids in every protein sue-specific genes, often via interactions with cell-specific [17]. Not only are the amino acids within the individual proteins [7-9]. The IL3 locus is an example of such a tar - zinc finger structures conserved, but there are also con - get. T Cell Receptor signaling leads to activation of an in - straints on the residues in the interfinger regions, with the ducible T cell-specific enhancer upstream of the IL3 gene, conserved linker sequence T/S-G-Q-R/K-P, suggesting containing NFAT and OCT1 binding sites. Studies have the zinc fingers act as a single unit [23]. The residues that shown the two transcription factors interact at the en - are directly in contact with the DNA, and therefore pro - hancer to synergistically activate T cell-specific IL3 ex - viding the specific base recognition, are the most con - pression [8]. Importantly, this system demonstrates how served parts
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