E2F7 regulates transcription and maturation of multiple microRNAs to restrain cell proliferation

• Published in: Nucleic acids research Vol. 44; no. 12; pp. 5557 - 5570
• Main Authors: Mitxelena, Jone, Apraiz, Aintzane, Vallejo-Rodríguez, Jon, Malumbres, Marcos, Zubiaga, Ana M
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 08.07.2016
• Subjects: Gene regulation, Chromatin and Epigenetics
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkw146

E2F transcription factors (E2F1-8) are known to coordinately regulate the expression of a plethora of target genes, including those coding for microRNAs (miRNAs), to control cell cycle progression. Recent work has described the atypical E2F factor E2F7 as a transcriptional repressor of cell cycle-related protein-coding genes. However, the contribution of E2F7 to miRNA gene expression during the cell cycle has not been defined. We have performed a genome-wide RNA sequencing analysis to identify E2F7-regulated miRNAs and show that E2F7 plays as a major role in the negative regulation of a set of miRNAs that promote cellular proliferation. We provide mechanistic evidence for an interplay between E2F7 and the canonical E2F factors E2F1-3 in the regulation of multiple miRNAs. We show that miR-25, -26a, -27b, -92a and -7 expression is controlled at the transcriptional level by the antagonistic activity of E2F7 and E2F1-3. By contrast, let-7 miRNA expression is controlled indirectly through a novel E2F/c-MYC/LIN28B axis, whereby E2F7 and E2F1-3 modulate c-MYC and LIN28B levels to impact let-7 miRNA processing and maturation. Taken together, our data uncover a new regulatory network involving transcriptional and post-transcriptional mechanisms controlled by E2F7 to restrain cell cycle progression through repression of proliferation-promoting miRNAs.