Role of epigenetic histone modifications during early embryonic stem cell differentiation

Abstract

Early embryonic stem cell differentiation includes “exit” from the pluripotent state followed by “commitment” to a specific lineage. During both of these processes there are genome‐wide changes in gene transcription levels that are regulated, at least in part, by epigenetic changes in histone tail modifications. We have demonstrated both global and gene specific changes in histone tail modifications. We focused on the role of these marks as they regulate the earliest stages of differentiation in mouse ES cells. Histone H3 phosphoacetylation (activating mark) is increased within the first 3 days of differentiation. Blocking general phosphorylation pathways markedly slowed exit from the pluripotent state. Blocking MSK1, the specific kinase responsible for phosphorylation on histone H3 still resulted in exit, but with diminished expression of early mesoderm markers. We also demonstrated a gene specific increase in acetylation (activating) of histones H3 and H4 and a global increase in acetylation of H4 as cells began lineage commitment. A pulse of the histone deacetylase inhibitor, TSA, maintained expression of markers of the undifferentiated state while also inducing expression of early mesoderm markers. TSA effects on later lineage commitment are being studied. We propose that epigenetic modifications play an important role in early cell fate decisions. This work was supported by NIH RO1 DK064243 from NIDDK.