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EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE71422 | GEO | 2015/11/02

SECONDARY ACCESSION(S): PRJNA291181

REPOSITORIES: GEO

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EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-11-02 | E-GEOD-71422 | biostudies-arrayexpress

EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression.

Project description:Fetal hemoglobin (HbF, ?2?2) induction is a well-validated strategy for sickle cell disease (SCD) treatment. Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces ?-globin expression. EHMT1/2 catalyze mono- and dimethylation of lysine 9 on histone 3 (H3K9), raising the possibility that H3K9Me2, a repressive chromatin mark, plays a role in silencing ?-globin expression. In primary human adult erythroid cells, UNC0638 and EHMT1 or EHMT2 short hairpin RNA-mediated knockdown significantly increased ?-globin expression, HbF synthesis, and the percentage of cells expressing HbF. At effective concentrations, UNC0638 did not alter cell morphology, proliferation, or erythroid differentiation of primary human CD34(+) hematopoietic stem and progenitor cells in culture ex vivo. In murine erythroleukemia cells, UNC0638 and Ehmt2 CRISPR/Cas9-mediated knockout both led to a marked increase in expression of embryonic ?-globin genes Hbb-?y and Hbb-?h1. In primary human adult erythroblasts, chromatin immunoprecipitation followed by sequencing analysis revealed that UNC0638 treatment leads to genome-wide depletion in H3K9Me2 and a concomitant increase in the activating mark H3K9Ac, which was especially pronounced at the ?-globin gene region. In RNA-sequencing analysis of erythroblasts, ?-globin genes were among the most significantly upregulated genes by UNC0638. Further increase in ?-globin expression in primary human adult erythroid cells was achieved by combining EHMT1/2 inhibition with the histone deacetylase inhibitor entinostat or hypomethylating agent decitabine. Our data provide genetic and pharmacologic evidence that EHMT1 and EHMT2 are epigenetic regulators involved in ?-globin repression and represent a novel therapeutic target for SCD.

| S-EPMC4608240 | biostudies-literature

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

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. ChIP-seq for 2 histone modifications and total H3 (for quantitative normalization) in biological triplicates of cord blood, adult bone marrow, and UNC0638-treated adult bone marrow.

2015-11-02 | E-GEOD-69516 | biostudies-arrayexpress

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.

2015-11-02 | GSE71421 | 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

HDAC1 and HDAC2 in fetal hemoglobin induction

Project description:This SuperSeries is composed of the SubSeries listed below.

2010-06-28 | GSE22369 | GEO

Potent and uniform fetal hemoglobin induction via base editing

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-04-28 | GSE228822 | GEO

NFI factors repress fetal hemoglobin in adult erythorid cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-03-23 | GSE180871 | GEO

Molecular Dissection of Polycomb Group Protein-mediated Fetal Hemoglobin Repression

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-01 | GSE218233 | GEO

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