PGE ₂ alters chromatin through H2A.Z-variant enhancer nucleosome modification to promote hematopoietic stem cell fate

Abstract

Prostaglandin E2 (PGE 2 ) and 16,16-dimethyl-PGE 2 (dmPGE 2 ) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem cell therapies [C. Cutler et al. Blood 122 , 3074–3081(2013); W. Goessling et al. Cell Stem Cell 8 , 445–458 (2011); W. Goessling et al. Cell 136 , 1136–1147 (2009)]. Here, we report that PGE 2 -induced changes in chromatin at enhancer regions through histone-variant H2A.Z permit acute inflammatory gene induction to promote HSPC fate. We found that dmPGE 2 -inducible enhancers retain MNase-accessible, H2A.Z-variant nucleosomes permissive of CREB transcription factor (TF) binding. CREB binding to enhancer nucleosomes following dmPGE 2 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 dmPGE 2 , lead to acute transcriptional changes and modify HSPC behavior to improve stem cell transplantation.

Profile of Leonard I. Zon

“…In Zon’s Inaugural Article ( 2 ), he and collaborators show how prostaglandin E2 chemically modifies certain histones—proteins that direct the tight, 3D packing of DNA. When the histones are modified, transcription factors can more easily bind, activating genes.…”

“…The compound has since progressed through clinical trials to help improve outcomes in patients receiving stem cell transplants for leukemia or lymphoma. In his Inaugural Article ( 2 ), Zon reveals the mechanism by which prostaglandin E2 exerts its effect; the chemical alters the chromatin structure of DNA near key stem cell genes.…”