Temporal perturbation of histone deacetylase activity reveals a requirement for HDAC1-3 in mesendoderm cell differentiation

Cell Rep. 2022 May 17;39(7):110818. doi: 10.1016/j.celrep.2022.110818.

Abstract

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.

Keywords: CP: Molecular biology; CP: Stem cell research; HDAC inhibitors; HDACs; cardiac development; cardiac differentiation; cardiac progenitor specification; cell fate; embryonic development; endoderm differentiation; epigenetics; genomics; hPSCs; histone deacetylases; mesendoderm specification; mesoderm differentiation; scRNA-seq; single-cell RNA sequencing; stem cell differentiation; transcriptomics.

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Chromatin / metabolism
  • Endoderm* / cytology
  • Endoderm* / enzymology
  • Endoderm* / metabolism
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylases* / genetics
  • Histone Deacetylases* / metabolism
  • Mice
  • Pluripotent Stem Cells* / cytology
  • Pluripotent Stem Cells* / enzymology
  • Pluripotent Stem Cells* / metabolism

Substances

  • Chromatin
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases
  • histone deacetylase 3