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.
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