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

Mol Cell. 2020 Feb 6;77(3):475-487.e11. doi: 10.1016/j.molcel.2019.10.020. Epub 2019 Nov 20.


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.

Keywords: 3D genome structure; ADPN; Alu elements; CTCF; H3K18ac; Pol II; TFIIIC; breast cancer; cell cycle; serum starvation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Alu Elements / genetics
  • Alu Elements / physiology*
  • Cell Line
  • Chromatin / metabolism
  • Chromatin / physiology
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation / genetics
  • Histones / genetics
  • Histones / metabolism*
  • Homeodomain Proteins / genetics
  • Humans
  • Nerve Tissue Proteins / genetics
  • Promoter Regions, Genetic / genetics
  • Protein Processing, Post-Translational
  • RNA Polymerase III / metabolism
  • Transcription Factors, TFIII / genetics
  • Transcription Factors, TFIII / metabolism*
  • Transcription, Genetic / genetics


  • ADNP protein, human
  • Chromatin
  • Histones
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Transcription Factors, TFIII
  • transcription factor TFIIIC
  • RNA Polymerase III