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

Audrey Sporrij, Avik Choudhuri, Meera Prasad, Brejnev Muhire, Eva M Fast, Margot E Manning, Jodi D Weiss, Michelle Koh, Song Yang, Robert E Kingston, Michael Y Tolstorukov, Hans Clevers, Leonard I Zon

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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 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 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.

Original languageEnglish
Pages (from-to)e2220613120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number19
DOIs
Publication statusPublished - 09 May 2023

Keywords

  • Nucleosomes
  • Histones/metabolism
  • Chromatin
  • Dinoprostone
  • Regulatory Sequences, Nucleic Acid
  • Chromatin Assembly and Disassembly

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