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Title: Alu retrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor
Authors: Morales Hernández, Antonio
González Rico, Francisco Javier
Román García, Ángel Carlos
Rico Leo, Eva María
Álvarez Barrientos, Alberto
Sánchez Ruiz, Laura
Macia Ortega, Ángela
Rodríguez Heras, Sara
García Pérez, José Luis
Merino Fernández, Jaime María
Fernández Salguero, Pedro María
Keywords: Diferenciación celular;Regulación de genes;Células de carcinoma;Elementos discretos de Alu;Cell differentiation;Gene regulation;Carcinoma cells;Discrete Alu elements
Issue Date: 2016
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.
ISSN: 0305-1048
DOI: 10.1093/nar/gkw095
Appears in Collections:DBYBM - Artículos

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