CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response

Grégoire Stik1, Enrique Vidal2, Mercedes Barrero2, Sergi Cuartero2,3, Maria Vila-Casadesús2, Julen Mendieta-Esteban4, Tian V Tian2,5, Jinmi Choi6, Clara Berenguer2,3, Amaya Abad2, Beatrice Borsari2, François le Dily2, Patrick Cramer6, Marc A Marti-Renom2,4,7, Ralph Stadhouders8,9, Thomas Graf10,11

  1. Centre for Genomic Regulation (CRG) and Institute of Science and Technology (BIST), Barcelona, Spain. gregoire.stik@crg.eu.
  2. Centre for Genomic Regulation (CRG) and Institute of Science and Technology (BIST), Barcelona, Spain.
  3. Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain.
  4. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  5. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  6. Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  7. ICREA, Barcelona, Spain.
  8. Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. r.stadhouders@erasmusmc.nl.
  9. Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands. r.stadhouders@erasmusmc.nl.
  10. Centre for Genomic Regulation (CRG) and Institute of Science and Technology (BIST), Barcelona, Spain. thomas.graf@crg.eu.
  11. Universitat Pompeu Fabra (UPF), Barcelona, Spain. thomas.graf@crg.eu.

Abstract

Three-dimensional organization of the genome is important for transcriptional regulation. In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs). Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the cohesin complex causes modest gene expression changes. In contrast, CTCF is required for cell cycle regulation, embryonic development and formation of various adult cell types. To uncouple the role of CTCF in cell-state transitions and cell proliferation, we studied the effect of CTCF depletion during the conversion of human leukemic B cells into macrophages with minimal cell division. CTCF depletion disrupts TAD organization but not cell transdifferentiation. In contrast, CTCF depletion in induced macrophages impairs the full-blown upregulation of inflammatory genes after exposure to endotoxin. Our results demonstrate that CTCF-dependent genome topology is not strictly required for a functional cell-fate conversion but facilitates a rapid and efficient response to an external stimulus.

Presented By Grégoire Stik

Genomics, Immunology & Microbiology, Genetics & Genome BiologyNicholas Liao2020-07 (Jul)