Sporrij A, Choudhuri A, Prasad M, Muhire B, Fast EM, Manning ME, Weiss JD, Koh M, Yang S, Kingston RE, Tolstorukov MY, Clevers H, Zon LI. 2023. PGE alters chromatin through H2A.Z-variant enhancer nucleosome modification to promote hematopoietic stem cell fate. Proceedings of the National Academy of Sciences of the United States of America. 120(19):e2220613120. Pubmed: 37126722 DOI:10.1073/pnas.2220613120


Prostaglandin E2 (PGE) and 16,16-dimethyl-PGE (dmPGE) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem cell therapies [C. Cutler , 3074-3081(2013); W. Goessling , 445-458 (2011); W. Goessling , 1136-1147 (2009)]. Here, we report that PGE-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-inducible enhancers retain MNase-accessible, H2A.Z-variant nucleosomes permissive of CREB transcription factor (TF) binding. CREB binding to enhancer nucleosomes following dmPGE 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, lead to acute transcriptional changes and modify HSPC behavior to improve stem cell transplantation.

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The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

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