PGE₂ alters chromatin through H2A.Z-variant enhancer nucleosome modification to promote hematopoietic stem cell fate.

Abstract

Prostaglandin E2 (PGE₂) and 16,16-dimethyl-PGE₂ (dmPGE₂) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem cell therapies [C. Cutler <i>et al.</i> <i>Blood</i> <b>122</b>, 3074-3081(2013); W. Goessling <i>et al.</i> <i>Cell Stem Cell</i> <b>8</b>, 445-458 (2011); W. Goessling <i>et al.</i> <i>Cell</i> <b>136</b>, 1136-1147 (2009)]. Here, we report that PGE₂-induced changes in chromatin at enhancer regions through histone-variant H2A.Z permit acute inflammatory gene induction to promote HSPC fate. We found that dmPGE₂-inducible enhancers retain MNase-accessible, H2A.Z-variant nucleosomes permissive of CREB transcription factor (TF) binding. CREB binding to enhancer nucleosomes following dmPGE₂ stimulation is concomitant with deposition of histone acetyltransferases p300 and Tip60 on chromatin. Subsequent H2A.Z acetylation improves chromatin accessibility at stimuli-responsive enhancers. Our findings support a model where histone-variant nucleosomes retained within inducible enhancers facilitate TF binding. Histone-variant acetylation by TF-associated nucleosome remodelers creates the accessible nucleosome landscape required for immediate enhancer activation and gene induction. Our work provides a mechanism through which inflammatory mediators, such as dmPGE₂, lead to acute transcriptional changes and modify HSPC behavior to improve stem cell transplantation.