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TFIIIC binding to Alu elements controls gene expression via chromatin looping and histone acetylation

By Roberto Ferrari, Lara Isabel de Llobet Cucalon, Chiara Di Vona, Fran├žois Le Dilly, Enrique Vidal, Antonios Lioutas, Javier Quilez Oliete, Laura Jochem, Erin Cutts, Giorgio Dieci, Alessandro Vannini, Martin Teichmann, Susana de la Luna, Miguel Beato

Posted 29 Oct 2018
bioRxiv DOI: 10.1101/455733 (published DOI: 10.1016/j.molcel.2019.10.020)

The mammalian genome is shaped by the expansion of repetitive elements that provide new regulatory networks for coordinated control of gene expression and genome folding. Alu elements (AEs) are selectively retained close to the transcription start site of genes, show proto-enhancer functions, correlate with the level of chromatin interactions and are recognized by transcription factor III (TFIIIC), but the relevance of all this is not clear. Here we report regulatory mechanisms that unveil a central role of AEs and TFIIIC in structurally and functionally modulating the genome via chromatin looping and histone acetylation. Upon serum deprivation, a subset of pre-marked AEs near cell cycle genes recruit TFIIIC to alter their chromatin accessibility via TFIIIC-mediated acetylation of histone H3 Lysine-18 (H3K18). This facilitates AEs contact with distant CTCF sites near other cell cycle genes promoters, which also become hyperacetylated at H3K18. These changes ensure basal transcription of crucial cell cycle genes, and are critical for their re-activation upon serum re-exposure. Our study reveals how direct manipulation of the epigenetic state of AEs by a general transcription factor adjusts 3D genome folding and gene expression. We anticipate that expansion of several families of repetitive elements during evolution might have served to generate new genomic cis-regulatory circuits enabling the coordinated regulation of a large set of genes relevant for cellular stress survival. As growth factor withdrawal is a situation relevant in cancer biology, our study identifies TFIIIC as a new potential target for clinical intervention.

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