title: Alu retrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor.
abstract: Cell differentiation is a central process in development and in cancer growth and dissemination. OCT4 (POU5F1) and NANOG are essential for cell stemness and pluripotency; yet, the mechanisms that regulate their expression remain largely unknown. Repetitive elements account for almost half of the Human Genome; still, their role in gene regulation is poorly understood. Here, we show that the dioxin receptor (AHR) leads to differentiation of human carcinoma cells through the transcriptional upregulation of Alu retrotransposons, whose RNA transcripts can repress pluripotency genes. Despite the genome-wide presence of Alu elements, we provide evidences that those located at the NANOG and OCT4 promoters bind AHR, are transcribed by RNA polymerase-III and repress NANOG and OCT4 in differentiated cells. OCT4 and NANOG repression likely involves processing of Alu-derived transcripts through the miRNA machinery involving the Microprocessor and RISC. Consistently, stable AHR knockdown led to basal undifferentiation, impaired Alus transcription and blockade of OCT4 and NANOG repression. We suggest that transcripts produced from AHR-regulated Alu retrotransposons may control the expression of stemness genes OCT4 and NANOG during differentiation of carcinoma cells. The control of discrete Alu elements by specific transcription factors may have a dynamic role in genome regulation under physiological and diseased conditions.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071-Badajoz, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Morales-Hernández
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071-Badajoz, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: González-Rico
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, 28002-Madrid, Spain.
authors.forename: Angel C
authors.initials: AC
authors.lastname: Román
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071-Badajoz, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Rico-Leo
authors.affiliation: Servicio de Técnicas Aplicadas a las Biociencias, Universidad de Extremadura, Avenida de Elvas s/n 06071-Badajoz, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Alvarez-Barrientos
authors.affiliation: GENYO. Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, Avda. de la Ilustración 114, PTS Granada, 18016-Granada, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez
authors.affiliation: GENYO. Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, Avda. de la Ilustración 114, PTS Granada, 18016-Granada, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Macia
authors.affiliation: GENYO. Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, Avda. de la Ilustración 114, PTS Granada, 18016-Granada, Spain.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Heras
authors.affiliation: GENYO. Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, Avda. de la Ilustración 114, PTS Granada, 18016-Granada, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: García-Pérez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071-Badajoz, Spain.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Merino
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071-Badajoz, Spain pmfersal@unex.es.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Fernández-Salguero
mesh_terms: D020087:Alu Elements; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D002277:Carcinoma / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D000071317:Nanog Homeobox Protein / Q000235:genetics; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D011401:Promoter Regions, Genetic; D012320:RNA Polymerase III / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism / Q000502:physiology*; D018243:Teratocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013724:Teratoma / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D012320:RNA Polymerase III; D018336:Receptors, Aryl Hydrocarbon; D014212:Tretinoin; C111235:AHR protein, human