title: A Chemical Biology Study of Human Pluripotent Stem Cells Unveils HSPA8 as a Key Regulator of Pluripotency.
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.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: geng2@illinois.edu.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Geng
authors.affiliation: Stem Cell Center, Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Lisa Corinna
authors.initials: LC
authors.lastname: Schuster
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Dana A
authors.initials: DA
authors.lastname: Lynn
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Austin
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Jason Daniel
authors.initials: JD
authors.lastname: Stoklosa
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Morrison
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D054852:Small Molecule Libraries; D004247:DNA