TFIIIC binding to alu elements controls gene expression via chromatin looping and histone acetylation
How repetitive elements, epigenetic modifications, and architectural proteins interact ensuring proper genome expression remains poorly understood. Here, we report regulatory mechanisms unveiling a central role of Alu elements (AEs) and RNA polymerase III transcription factor C (TFIIIC) in structurally and functionally modulating the genome via chromatin looping and histone acetylation. Upon serum deprivation, a subset of AEs pre-marked by the activity-dependent neuroprotector homeobox Protein (ADNP) and located near cell-cycle genes recruits TFIIIC, which alters their chromatin accessibility by direct acetylation of histone H3 lysine-18 (H3K18). This facilitates the contacts of AEs with distant CTCF sites near promoter of other cell-cycle genes, which also become hyperacetylated at H3K18. These changes ensure basal transcription of 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 regulates 3D genome folding and expression. ; This work was supported by the Spanish Ministry of Economy and Competitiveness Centro de Excelencia Severo Ochoa 2013–2017 SEV-2012-0208 (to CRG) and BFU2016-76141-P (to S.d.l.L.); ACER (to CRG); Italian Association for Cancer Research (AIRC, grant IG16877 to G.D.); the Cancer Research UK Programme Foundation (CR-UK C47547/A21536 to A.V.); a Wellcome Trust Investigator Award (200818/Z/16/Z to A.V.); and the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007–2013/ERC Synergy grant agreement 609989-4DGenome to M.B.). We acknowledge the support of the Spanish Ministry of Science, Innovation, and Universities to the EMBL partnership, the CERCA Programme/Generalitat de Catalunya , and the Centro de Excelencia Severo Ochoa. The ERC provided funding for the open access charge. The proteomics analyses were performed at the CRG/UPF Proteomics Unit (part of the of Proteored, PRB3; supported by grant PT17/0019 [ISCIII and ERDF]). This work was also supported by the Ligue Contre le Cancer (to M.T.)