BRD4 orchestrates genome folding to promote neural crest differentiation

Nat Genet. 2021 Oct;53(10):1480-1492. doi: 10.1038/s41588-021-00934-8. Epub 2021 Oct 5.

Abstract

Higher-order chromatin structure regulates gene expression, and mutations in proteins mediating genome folding underlie developmental disorders known as cohesinopathies. However, the relationship between three-dimensional genome organization and embryonic development remains unclear. Here we define a role for bromodomain-containing protein 4 (BRD4) in genome folding, and leverage it to understand the importance of genome folding in neural crest progenitor differentiation. Brd4 deletion in neural crest results in cohesinopathy-like phenotypes. BRD4 interacts with NIPBL, a cohesin agonist, and BRD4 depletion or loss of the BRD4-NIPBL interaction reduces NIPBL occupancy, suggesting that BRD4 stabilizes NIPBL on chromatin. Chromatin interaction mapping and imaging experiments demonstrate that BRD4 depletion results in compromised genome folding and loop extrusion. Finally, mutation of individual BRD4 amino acids that mediate an interaction with NIPBL impedes neural crest differentiation into smooth muscle. Remarkably, loss of WAPL, a cohesin antagonist, rescues attenuated smooth muscle differentiation resulting from BRD4 loss. Collectively, our data reveal that BRD4 choreographs genome folding and illustrates the relevance of balancing cohesin activity for progenitor differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation* / genetics
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • Gene Expression Regulation
  • Genome*
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Integrases / metabolism
  • Mice
  • Models, Biological
  • Mouse Embryonic Stem Cells / metabolism
  • Muscle Cells / cytology
  • Neural Crest / cytology*
  • Neural Crest / metabolism
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Domains
  • Proteolysis
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • NIPBL protein, human
  • Nuclear Proteins
  • Transcription Factors
  • cohesins
  • Cre recombinase
  • Integrases