TFIIIC Binding to Alu Elements Controls Gene Expression via Chromatin Looping and Histone Acetylation

• Published in: Molecular cell Vol. 77; no. 3; pp. 475 - 487.e11
• Main Authors: Ferrari, Roberto, de Llobet Cucalon, Lara Isabel, Di Vona, Chiara, Le Dilly, François, Vidal, Enrique, Lioutas, Antonios, Oliete, Javier Quilez, Jochem, Laura, Cutts, Erin, Dieci, Giorgio, Vannini, Alessandro, Teichmann, Martin, de la Luna, Susana, Beato, Miguel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-02-2020; Cell Press
• Subjects: 3D genome structure; Acetylation; ADPN; Alu elements; Alu Elements - genetics; Alu Elements - physiology; breast cancer; cell cycle; Cell Line; Chromatin - metabolism; Chromatin - physiology; CTCF; Epigenesis, Genetic - genetics; Gene Expression Regulation - genetics; H3K18ac; Histones - genetics; Histones - metabolism; Homeodomain Proteins - genetics; Humans; Nerve Tissue Proteins - genetics; Pol II; Promoter Regions, Genetic - genetics; Protein Processing, Post-Translational; RNA Polymerase III - metabolism; serum starvation; TFIIIC; Transcription Factors, TFIII - genetics; Transcription Factors, TFIII - metabolism; Transcription, Genetic - genetics; serum starvation; Pol II; cell cycle; H3K18ac; Alu elements; breast cancer; CTCF; 3D genome structure; TFIIIC; ADPN
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.10.020

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.
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•Serum starvation recruits TFIIIC at ADNP-bound Alu Elements (AEs) near Pol II genes•TFIIIC-associated histone acetylase activity acetylates H3K18 over the bound AEs•TFIIIC-bound acetylated AEs loop to contact CTCF at distal cell-cycle genes’ promoters•CTCF-TFIIIC interaction ensures rapid cell-cycle genes’ reactivation on serum exposure
Repetitive elements shape genome structure and function. Ferrari et al. find that cells respond to serum deprivation by redirecting the general transcription factor TFIIIC to acetylate ADNP-bound Alu elements in order to rewire the 3D genome architecture via CTCF looping, ultimately sustaining steady-state levels of cell-cycle-regulated gene expression.