Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7886
E2F7 regulates transcription and maturation of multiple microRNAs to restrain cell proliferation
Nucleic Acids Res. 2016 Mar 9. pii: 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.
This work was supported by the Spanish Ministry [SAF2012-33551, co-funded by the European RegionalDevelopment fund to A.M.Z., SAF2012-38215 to M.M.,SAF2014-57791-REDC to A.M.Z. and to M.M.]; BasqueGovernment [IT634-13 to A.M.Z.]; University of theBasque Country UPV/EHU [UFI1120 to A.M.Z.]; Excellence Network CellSYS [BFU2014-52125-REDT to M.M.];Comunidad de Madrid [S2010/BMD-2470 to M.M.];Basque Government Fellowship for graduate studies (to J.M.). Funding for open access charge: Basque Government [IT634-13]. Conflict of interest statement. None declared.
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