Temporal perturbation of histone deacetylase activity reveals a requirement for HDAC1–3 in mesendoderm cell differentiation
Enakshi Sinniah,
Zhixuan Wu,
Sophie Shen,
Marina Naval-Sanchez,
Xiaoli Chen,
Junxian Lim,
Abbigail Helfer,
Abishek Iyer,
Jiahui Tng,
Andrew J. Lucke,
Robert C. Reid,
Meredith A. Redd,
Christian M. Nefzger,
David P. Fairlie,
Nathan J. Palpant
Affiliations
Enakshi Sinniah
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Zhixuan Wu
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Sophie Shen
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Marina Naval-Sanchez
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Xiaoli Chen
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Junxian Lim
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; ARC Centre of Excellence for Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Abbigail Helfer
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Abishek Iyer
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; ARC Centre of Excellence for Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Jiahui Tng
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; ARC Centre of Excellence for Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Andrew J. Lucke
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; ARC Centre of Excellence for Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Robert C. Reid
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; ARC Centre of Excellence for Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Meredith A. Redd
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Christian M. Nefzger
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
David P. Fairlie
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; ARC Centre of Excellence for Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Nathan J. Palpant
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; Corresponding author
Summary: Histone deacetylases (HDACs) are a class of enzymes that control chromatin state and influence cell fate. We evaluated the chromatin accessibility and transcriptome dynamics of zinc-containing HDACs during cell differentiation in vitro coupled with chemical perturbation to identify the role of HDACs in mesendoderm cell fate specification. Single-cell RNA sequencing analyses of HDAC expression during human pluripotent stem cell (hPSC) differentiation in vitro and mouse gastrulation in vivo reveal a unique association of HDAC1 and -3 with mesendoderm gene programs during exit from pluripotency. Functional perturbation with small molecules reveals that inhibition of HDAC1 and -3, but not HDAC2, induces mesoderm while impeding endoderm and early cardiac progenitor specification. These data identify unique biological functions of the structurally homologous enzymes HDAC1–3 in influencing hPSC differentiation from pluripotency toward mesendodermal and cardiac progenitor populations.
