PGE Alters Chromatin Through H2A.Z-variant Enhancer Nucleosome Modification to Promote Hematopoietic Stem Cell Fate

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2023 May 1

PMID 37126722

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The "Ins and Outs and What-Abouts" of H2A.Z: A tribute to C. David Allis.

Diegmuller F, Leers J, Hake S J Biol Chem. 2025; 301(2):108154.

PMID: 39761855 PMC: 11808731. DOI: 10.1016/j.jbc.2025.108154.

Multifunctional histone variants in genome function.

Wong L, Tremethick D Nat Rev Genet. 2024; 26(2):82-104.

PMID: 39138293 DOI: 10.1038/s41576-024-00759-1.

Profile of Leonard I. Zon.

Williams S Proc Natl Acad Sci U S A. 2023; 120(31):e2310767120.

PMID: 37467283 PMC: 10400938. DOI: 10.1073/pnas.2310767120.

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

Sporrij A, Choudhuri A, Prasad M, Muhire B, Fast E, Manning M Proc Natl Acad Sci U S A. 2023; 120(19):e2220613120.

PMID: 37126722 PMC: 10175842. DOI: 10.1073/pnas.2220613120.

References

Gavaravarapu S, Kamine J . Tip60 inhibits activation of CREB protein by protein kinase A. Biochem Biophys Res Commun. 2000; 269(3):758-66. DOI: 10.1006/bbrc.2000.2358. View

Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S . Latent enhancers activated by stimulation in differentiated cells. Cell. 2013; 152(1-2):157-71. DOI: 10.1016/j.cell.2012.12.018. View

Wu D, Sunkel B, Chen Z, Liu X, Ye Z, Li Q . Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer. Nucleic Acids Res. 2014; 42(6):3607-22. PMC: 3973339. DOI: 10.1093/nar/gkt1382. View

Mieczkowski J, Cook A, Bowman S, Mueller B, Alver B, Kundu S . MNase titration reveals differences between nucleosome occupancy and chromatin accessibility. Nat Commun. 2016; 7:11485. PMC: 4859066. DOI: 10.1038/ncomms11485. View

Perlin J, Sporrij A, Zon L . Blood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment. J Mol Med (Berl). 2017; 95(8):809-819. PMC: 5558790. DOI: 10.1007/s00109-017-1559-8. View

Hottiger M, Nabel G . Interaction of human immunodeficiency virus type 1 Tat with the transcriptional coactivators p300 and CREB binding protein. J Virol. 1998; 72(10):8252-6. PMC: 110181. DOI: 10.1128/JVI.72.10.8252-8256.1998. View

de Nadal E, Ammerer G, Posas F . Controlling gene expression in response to stress. Nat Rev Genet. 2011; 12(12):833-45. DOI: 10.1038/nrg3055. View

John S, Sabo P, Thurman R, Sung M, Biddie S, Johnson T . Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet. 2011; 43(3):264-8. PMC: 6386452. DOI: 10.1038/ng.759. View

Miller S . Prostaglandins in health and disease: an overview. Semin Arthritis Rheum. 2006; 36(1):37-49. DOI: 10.1016/j.semarthrit.2006.03.005. View

10.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

11.

Trompouki E, Bowman T, Lawton L, Fan Z, Wu D, DiBiase A . Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell. 2011; 147(3):577-89. PMC: 3219441. DOI: 10.1016/j.cell.2011.09.044. View

12.

Jin C, Felsenfeld G . Nucleosome stability mediated by histone variants H3.3 and H2A.Z. Genes Dev. 2007; 21(12):1519-29. PMC: 1891429. DOI: 10.1101/gad.1547707. View

13.

Fast E, Toomey M, Panaram K, Desjardins D, Kolaczyk E, Frydman H . Wolbachia enhance Drosophila stem cell proliferation and target the germline stem cell niche. Science. 2011; 334(6058):990-2. PMC: 4030408. DOI: 10.1126/science.1209609. View

14.

de Pater E, Kaimakis P, Vink C, Yokomizo T, Yamada-Inagawa T, van der Linden R . Gata2 is required for HSC generation and survival. J Exp Med. 2013; 210(13):2843-50. PMC: 3865477. DOI: 10.1084/jem.20130751. View

15.

North T, Goessling W, Walkley C, Lengerke C, Kopani K, Lord A . Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007; 447(7147):1007-11. PMC: 2775137. DOI: 10.1038/nature05883. View

16.

Merika M, Williams A, Chen G, Collins T, Thanos D . Recruitment of CBP/p300 by the IFN beta enhanceosome is required for synergistic activation of transcription. Mol Cell. 1998; 1(2):277-87. DOI: 10.1016/s1097-2765(00)80028-3. View

17.

Hu G, Cui K, Northrup D, Liu C, Wang C, Tang Q . H2A.Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation. Cell Stem Cell. 2012; 12(2):180-92. PMC: 3570599. DOI: 10.1016/j.stem.2012.11.003. View

18.

Ramani V, Qiu R, Shendure J . High Sensitivity Profiling of Chromatin Structure by MNase-SSP. Cell Rep. 2019; 26(9):2465-2476.e4. PMC: 6582983. DOI: 10.1016/j.celrep.2019.02.007. View

19.

Colino-Sanguino Y, Clark S, Valdes-Mora F . H2A.Z acetylation and transcription: ready, steady, go!. Epigenomics. 2016; 8(5):583-6. DOI: 10.2217/epi-2016-0016. View

20.

Gevry N, Hardy S, Jacques P, Laflamme L, Svotelis A, Robert F . Histone H2A.Z is essential for estrogen receptor signaling. Genes Dev. 2009; 23(13):1522-33. PMC: 2704467. DOI: 10.1101/gad.1787109. View