CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Nat Commun. 2022 Nov 16;13(1):7002. doi: 10.1038/s41467-022-34476-2.


Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CREB-Binding Protein* / genetics
  • CREB-Binding Protein* / metabolism
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Heat-Shock Proteins* / genetics
  • Heat-Shock Proteins* / metabolism
  • Histones / genetics
  • Humans
  • Mutation
  • Neurodevelopmental Disorders* / genetics
  • Neurodevelopmental Disorders* / pathology
  • Rubinstein-Taybi Syndrome* / genetics
  • Rubinstein-Taybi Syndrome* / pathology
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism


  • CREB-Binding Protein
  • Heat-Shock Proteins
  • Histones
  • HSF2 protein, human
  • Transcription Factors
  • EP300 protein, human
  • E1A-Associated p300 Protein