Wang Qiang, Geng Zhuangzhuang, Gong Yi, Warren Kaitlyn, Zheng Haiyan, Imamura Yuka, Gao Zhonghua
Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, United States.
National Institute on Aging, Bethesda, MD 20892, United States.
Stem Cell Res. 2018 Dec;33:206-214. doi: 10.1016/j.scr.2018.10.023. Epub 2018 Nov 12.
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.
近期对多梳抑制复合物（PRC）的研究揭示了其在转录激活中出人意料的作用，但其潜在机制仍知之甚少。我们之前鉴定出一种包含自闭症易感候选基因2（AUTS2）的1型PRC（PRC1），它对神经元基因的转录起正向调节作用。然而，PRC1-AUTS2复合物影响神经发育的机制尚不清楚。在此我们证明，WDR68不仅是PRC1-AUTS2复合物的一个组成部分，而且PRC1-AUTS2介导的转录激活也需要它。此外，在小鼠胚胎干细胞中缺失Wdr68会导致神经元分化缺陷，但不影响自我更新。通过转录组分析，我们发现许多负责神经元分化的基因在Wdr68缺陷的神经祖细胞中表达下调。这些基因包括那些被PRC1-AUTS2复合物靶向的基因。总之，我们的研究发现了活性PRC1复合物中一个此前未知但必不可少的组成部分，并证明了其在调节对神经元分化重要的基因表达中的作用。
