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Chemical inhibition of Histone Deacetylases 1 and 2 induces fetal hemoglobin through activation of Gata2

ABSTRACT: Chemical inhibition of Histone Deacetylases 1 and 2 induces fetal hemoglobin through activation of Gata2

PROVIDER: PRJNA259549 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR1559023.fastq.gz	Fastqsanger.gz
	SRR1559024.fastq.gz	Fastqsanger.gz
	SRR1559025.fastq.gz	Fastqsanger.gz
	SRR1559026.fastq.gz	Fastqsanger.gz
	SRR1559027.fastq.gz	Fastqsanger.gz

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Chemical Inhibition of Histone Deacetylases 1 and 2 Induces Fetal Hemoglobin through Activation of GATA2.

Project description:Therapeutic intervention aimed at reactivation of fetal hemoglobin protein (HbF) is a promising approach for ameliorating sickle cell disease (SCD) and ?-thalassemia. Previous studies showed genetic knockdown of histone deacetylase (HDAC) 1 or 2 is sufficient to induce HbF. Here we show that ACY-957, a selective chemical inhibitor of HDAC1 and 2 (HDAC1/2), elicits a dose and time dependent induction of ?-globin mRNA (HBG) and HbF in cultured primary cells derived from healthy individuals and sickle cell patients. Gene expression profiling of erythroid progenitors treated with ACY-957 identified global changes in gene expression that were significantly enriched in genes previously shown to be affected by HDAC1 or 2 knockdown. These genes included GATA2, which was induced greater than 3-fold. Lentiviral overexpression of GATA2 in primary erythroid progenitors increased HBG, and reduced adult ?-globin mRNA (HBB). Furthermore, knockdown of GATA2 attenuated HBG induction by ACY-957. Chromatin immunoprecipitation and sequencing (ChIP-Seq) of primary erythroid progenitors demonstrated that HDAC1 and 2 occupancy was highly correlated throughout the GATA2 locus and that HDAC1/2 inhibition led to elevated histone acetylation at well-known GATA2 autoregulatory regions. The GATA2 protein itself also showed increased binding at these regions in response to ACY-957 treatment. These data show that chemical inhibition of HDAC1/2 induces HBG and suggest that this effect is mediated, at least in part, by histone acetylation-induced activation of the GATA2 gene.

| S-EPMC4830539 | biostudies-literature

microRNA expression profiles of reticulocytes for hereditary persistence of fetal hemoglobin and β-thalssemia minor with high fetal hemoglobin.

Project description:We used microarrays to investigate differential microRNA (miRNA) expression in reticulocytes comparing reticulocytes from control individuals with normal fetal hemoglobin (HbF) level to hereditary persistence of fetal hemoglobin (HPFH) and β-thalssemia minor with high HbF, and try to find out some miRNAs associated with the mechanisms of HbF induction.

2018-01-01 | GSE93973 | GEO

Critical Vulnerabilities of the NuRD Complex for Fetal Hemoglobin Control

Project description:High-resolution CRISPR functional genomics reveals critical vulnerabilities of the NuRD complex for fetal hemoglobin control

2019-05-22 | PXD009793 | Pride

The long noncoding RNA expression profiles of reticulocytes for hereditary persistence of fetal hemoglobin and β-thalssemia minor with high fetal hemoglobin.

Project description:To explore long noncoding RNA (lncRNA) expression and the biological functions of lncRNAs in fetal hemoglobin (HbF) induction, we surveyed lncRNA and mRNA expression profiles using circulating reticulocytes isolated from individuals with hereditary persistence of fetal hemoglobin (HPFH) and β-thalassaemia minor with high HbF.

2018-01-01 | GSE93971 | GEO

Chemical inhibition of Histone Deacetylases 1 and 2 induces fetal hemoglobin through activation of Gata2

Project description:This SuperSeries is composed of the SubSeries GSE60791 and GSE60792.

2016-04-11 | GSE60793 | GEO

EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression [ChIP-seq]

Project description:Using UNC0638 and genetic assays to inhibit EHMT1/2 and derepress fetal hemoglobin in adult hematopoietic cells.

2015-11-02 | GSE69516 | GEO

EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression [RNA-seq]

Project description:Using UNC0638 and genetic assays to inhibit EHMT1/2 and derepress fetal hemoglobin in adult hematopoietic cells.

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GATA2 restricts genomic actions of innate immune mediators on fetal hematopoietic progenitor cells

Project description:Innate immune signaling protects against pathogens, controls hematopoietic development and functions in oncogenesis, yet the relationship between these mechanisms is incompletely defined. Downregulating the GATA2 transcription factor in fetal hematopoietic progenitor cells upregulates genes encoding innate immune regulators, increases Interferon-g (IFNg) signaling and disrupts differentiation. Here, we demonstrate that deletion of an enhancer that confers GATA2 expression in fetal progenitor cells elevated Toll-Like Receptor (TLR) TLR1/2 and TLR2/6 expression and signaling. Genetic rescue by expressing GATA2 downregulated the elevated TLR signaling. IFNg amplified TLR1/2 and TLR2/6 signaling in GATA2-deficient progenitor cells, synergistically activating cytokine/chemokine genes and elevating cytokine/chemokine production in their myeloid cell progeny. Genome-wide analysis of how IFNg and TLR signaling remodels the progenitor cell transcriptome in GATA2-deficient cells revealed exaggerated responses at innate immune genes harboring motifs for signal-dependent transcription factors. Thus, GATA2 establishes a transcriptome that constrains innate immune signaling, and insufficient GATA2 renders fetal progenitor cells hypersensitive to innate immune signaling.

2023-04-15 | GSE218445 | GEO

EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression [RNA-seq]

Project description:Using UNC0638 and genetic assays to inhibit EHMT1/2 and derepress fetal hemoglobin in adult hematopoietic cells. RNA-Seq in primary adult human erythroid cells treated with UNC0638 or the vehicle control (DMSO) in biological triplicates.

2015-11-02 | E-GEOD-71421 | biostudies-arrayexpress

Genome-wide DNA methylation differences between ex vivo differentiated cells that recapitulate the fetal-to-adult hemoglobin switch

Project description:The aim of this study is to characterize de genome-wide DNA methylation changes that occur during the fetal-to-adult hemoglobin switch in erythroblasts. We differentiated CD34+ hematopoietic progenitor cells collected for either fetal liver or bone marrow into erythroblasts. After differentiation, cells produce respectively fetal hemoglobin and adult hemoglobin in majority. We compared genome-wide DNA methylation states of fetal-stage erythroblasts to those of adult-stage erythroblasts.

2014-12-02 | GSE56491 | GEO

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