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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229399 | GEO | 2024/06/10

REPOSITORIES: GEO

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (RNA-Seq)

Project description:Hematopoietic stem and progenitor cells (HSPCs) need require tight transcriptional regulation. In-depth knowledge on how epigenetic mechanisms regulate chromatin landscape in order to control gene expression, particularly in response to external stimuli, will be key to understand the pathogenesis of hematologic disorders and improve blood stem cell-based therapies. Prostaglandin E2 (PGE2) and its metabolically resistant analog 16,16-dimethyl-PGE2 (dmPGE2) were previously identified as a potent external stimulus to enhance HSPC engraftment. PGE2 has been evaluated in various clinical trials to improve engraftment of stem cells. To understand the mechanism of gene expression changes, Wwe identified that dmPGE2 mediates chromatin flexibility at HSPC-specific enhancers through histone-variant H2A.Z acetylation to promote master transcription factor (TF) binding and reinforce expression of genes involved in stem cell fate and engraftment.

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (Mnase-Seq)

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (ChIP-Seq)

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (ATAC-Seq)

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

Project description: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.

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate

Project description:PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (ATAC-Seq)

Project description:PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (ATAC-Seq)

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (Mnase-Seq)

Project description:PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (Mnase-Seq)

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (ChIP-Seq)

Project description:PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (ChIP-Seq)

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PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (RNA-Seq)

Project description:PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (RNA-Seq)

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