WDR68 is essential for the transcriptional activation of the PRC1-AUTS2 complex and neuronal differentiation of mouse embryonic stem cells

Stem Cell Res. 2018 Dec;33:206-214. doi: 10.1016/j.scr.2018.10.023. Epub 2018 Nov 12.

Abstract

Recent studies on Polycomb repressive complexes (PRC) reveal a surprising role in transcriptional activation, yet the underlying mechanism remains poorly understood. We previously identified a type 1 PRC (PRC1) that contains Autism Susceptibility Candidate 2 (AUTS2), which positively regulates transcription of neuronal genes. However, the mechanism by which the PRC1-AUTS2 complex influences neurodevelopment is unclear. Here we demonstrate that WDR68 is not only an integral component of the PRC1-AUTS2 complex, but it is also required for PRC1-AUTS2-mediated transcription activation. Furthermore, deletion of Wdr68 in mouse embryonic stem cells leads to defects in neuronal differentiation without affecting self-renewal. Through transcriptomic analysis, we found that many genes responsible for neuronal differentiation are down-regulated in Wdr68 deficient neural progenitors. These genes include those targeted by the PRC1-AUTS2 complex. In summary, our studies uncovered a previously unknown but essential component of the active PRC1 complex and evidence of its role in regulating the expression of genes that are important for neuronal differentiation.

Keywords: Differentiation; Epigenetics; Polycomb; Protein complex; Stem cells; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Mice
  • Mouse Embryonic Stem Cells / metabolism*
  • Nuclear Proteins / genetics*
  • Polycomb-Group Proteins / genetics*
  • Transcriptional Activation

Substances

  • Adaptor Proteins, Signal Transducing
  • Dcaf7 protein, mouse
  • Nuclear Proteins
  • Polycomb-Group Proteins