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

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

Author information

1
Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, United States.
2
National Institute on Aging, Bethesda, MD 20892, United States.
3
Biological Mass Spectrometry Facility at Robert Wood Johnson Medical School and Rutgers, The State University of New, Piscataway, NJ 08854, Jersey.
4
Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, United States; Departments of Pharmacology and Institute for Personalized Medicine, Penn State College of Medicine, Hershey, PA 17033, United States.
5
Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, United States; Penn State Hershey Cancer Institute, Hershey, PA 17033, United States; The Stem Cell and Regenerative Biology Program, Penn State College of Medicine, Hershey, PA 17033, United States. Electronic address: zgao1@pennstatehealth.psu.edu.

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

PMID:
30448639
DOI:
10.1016/j.scr.2018.10.023
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