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      TERT Promotes Epithelial Proliferation through Transcriptional Control of a Myc- and Wnt-Related Developmental Program

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          Abstract

          Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT ci) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT ci retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

          Author Summary

          Stem cells and progenitor cells within a tissue are required to maintain tissue homeostasis and to repair tissues after injury by giving rise to differentiated daughter cells. Many progenitor cells express telomerase, a reverse transcriptase enzyme that adds DNA repeats to telomeres, the protective structures that cap chromosome ends. Telomere addition by telomerase is important for normal progenitor cell function and is crucial for enabling cancer cells to divide an unlimited number of times. In addition to its telomere-lengthening function, telomerase reverse transcriptase (TERT) can directly activate quiescent epidermal stem cells. However, the mechanism underlying this novel function for TERT is still not understood. In this study, we demonstrate that the catalytic activity of TERT is dispensable for its ability to activate tissue progenitor cells in vivo. Furthermore, using gene microarrays, we show that TERT controls a developmental program that overlaps the natural transcriptional program of hair follicle cycling in mouse skin. Using pattern-matching algorithms, we find that the TERT-controlled genetic program significantly resembles programs regulated by Myc and Wnt, two pathways critical for stem cell function and tumorigenesis. This paper reveals critical new insights into novel mechanisms of non-telomerase functions of TERT, identifying TERT as a developmental regulator linked to control of transcriptional responses.

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          Most cited references50

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          DAVID: Database for Annotation, Visualization, and Integrated Discovery.

          Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.
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            Identification of c-MYC as a target of the APC pathway.

            The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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              Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.

              Comprehensive identification of all functional elements encoded in the human genome is a fundamental need in biomedical research. Here, we present a comparative analysis of the human, mouse, rat and dog genomes to create a systematic catalogue of common regulatory motifs in promoters and 3' untranslated regions (3' UTRs). The promoter analysis yields 174 candidate motifs, including most previously known transcription-factor binding sites and 105 new motifs. The 3'-UTR analysis yields 106 motifs likely to be involved in post-transcriptional regulation. Nearly one-half are associated with microRNAs (miRNAs), leading to the discovery of many new miRNA genes and their likely target genes. Our results suggest that previous estimates of the number of human miRNA genes were low, and that miRNAs regulate at least 20% of human genes. The overall results provide a systematic view of gene regulation in the human, which will be refined as additional mammalian genomes become available.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                plge
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                January 2008
                18 January 2008
                7 December 2008
                : 4
                : 1
                : e10
                Affiliations
                [1 ] Department of Medicine, Stanford School of Medicine, Stanford, California, United States of America
                [2 ] Cancer Biology Program, Stanford School of Medicine, Stanford, California, United States of America
                [3 ] Department of Genetics, Stanford School of Medicine, Stanford, California, United States of America
                [4 ] Biomedical Informatics Program, Stanford School of Medicine, Stanford, California, United States of America
                [5 ] Department of Computer Science, Stanford University, Stanford, California, United States of America
                [6 ] Department of Developmental Biology, Stanford School of Medicine, Stanford, California, United States of America
                The Jackson Laboratory, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: sartandi@ 123456stanford.edu
                Article
                07-PLGE-RA-0657R2 plge-04-01-16
                10.1371/journal.pgen.0040010
                2211538
                18208333
                310bca95-f056-4f77-a96b-80cb07be7149
                Copyright: © 2008 Choi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 16 August 2007
                : 6 December 2007
                Page count
                Pages: 15
                Categories
                Research Article
                Computational Biology
                Developmental Biology
                Genetics and Genomics
                Mus (Mouse)
                Custom metadata
                Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, et al. (2008) TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet 4(1): e10. doi: 10.1371/journal.pgen.0040010

                Genetics
                Genetics

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