A Chemical Biology Study of Human Pluripotent Stem Cells Unveils HSPA8 as a Key Regulator of Pluripotency

  • Stem Cell Reports. 2015 Dec 8;5(6):1143-1154. doi: 10.1016/j.stemcr.2015.09.023.
Yijie Geng  1 ,  Yongfeng Zhao  2 ,  Lisa Corinna Schuster  3 ,  Bradley Feng  3 ,  Dana A Lynn  3 ,  Katherine M Austin  3 ,  Jason Daniel Stoklosa  3 ,  Joseph D Morrison  3
Affiliations
  • 1. Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: [email protected].
  • 2. Stem Cell Center, Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, USA.
  • 3. Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
PMID: 26549849 DOI: 10.1016/j.stemcr.2015.09.023
Abstract

Chemical biology methods such as high-throughput screening (HTS) and affinity-based target identification can be used to probe biological systems on a biomacromolecule level, providing valuable insights into the molecular mechanisms of those systems. Here, by establishing a human embryonal carcinoma cell-based HTS platform, we screened 171,077 small molecules for regulators of pluripotency and identified a small molecule, Displurigen, that potently disrupts hESC pluripotency by targeting heat shock 70-kDa protein 8 (HSPA8), the constitutively expressed member of the 70-kDa heat shock protein family, as elucidated using affinity-based target identification techniques and confirmed by loss-of-function and gain-of-function assays. We demonstrated that HSPA8 maintains pluripotency by binding to the master pluripotency regulator OCT4 and facilitating its DNA-binding activity.

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