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

Autor: Sporrij A; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Choudhuri A; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Prasad M; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Muhire B; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Fast EM; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Manning ME; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Weiss JD; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Koh M; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Yang S; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115., Kingston RE; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Tolstorukov MY; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA 02215., Clevers H; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands.; Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CS, The Netherlands., Zon LI; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115.; HHMI, Harvard Stem Cell Institute, Boston, MA 02115.; Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 May 09; Vol. 120 (19), pp. e2220613120. Date of Electronic Publication: 2023 May 01.
DOI: 10.1073/pnas.2220613120
Abstrakt: 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.
Databáze: MEDLINE
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