NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain

Mol Cell. 2021 Nov 18;81(22):4663-4676.e8. doi: 10.1016/j.molcel.2021.09.020. Epub 2021 Oct 11.


The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.

Keywords: AUTS2; NRF1; P300; RSTS; active transcription; brain development; ncPRC1.3; polycomb.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism*
  • CREB-Binding Protein / genetics*
  • Cell Differentiation
  • Chromatin / chemistry
  • Cytoskeletal Proteins / metabolism*
  • E1A-Associated p300 Protein / genetics*
  • Embryonic Stem Cells / metabolism*
  • Female
  • Genomics
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Male
  • Mice
  • Neurons / metabolism
  • Nuclear Respiratory Factor 1 / metabolism*
  • Protein Binding
  • Protein Domains
  • Proteomics
  • Transcription Factors / metabolism*
  • Transcriptional Activation


  • AUTS2 protein, human
  • Auts2 protein, mouse
  • Chromatin
  • Cytoskeletal Proteins
  • NRF1 protein, human
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Transcription Factors
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, mouse
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Ep300 protein, mouse