Cell Reports (May 2022)

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

Journal volume & issue
Vol. 39, no. 7
p. 110818

Abstract

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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.

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