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A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for novel therapeutic compounds

ABSTRACT: Fetal hemoglobin reporter cells for drug discovery

PROVIDER: PRJEB67342 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR13364329.fastq.gz	Fastqsanger.gz
	ERR13364330.fastq.gz	Fastqsanger.gz
	ERR13364331.fastq.gz	Fastqsanger.gz
	ERR13364332.fastq.gz	Fastqsanger.gz
	ERR13364333.fastq.gz	Fastqsanger.gz

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A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for therapeutic compounds.

Project description:Reactivation of fetal hemoglobin expression alleviates the symptoms associated with β-globinopathies, severe hereditary diseases with significant global health implications due to their high morbidity and mortality rates. The symptoms emerge following the postnatal transition from fetal-to-adult hemoglobin expression. Extensive research has focused on inducing the expression of the fetal γ-globin subunit to reverse this switch and ameliorate these symptoms. Despite decades of research, only one compound, hydroxyurea, found its way to the clinic as an inducer of fetal hemoglobin. Unfortunately, its efficacy varies among patients, highlighting the need for more effective treatments. Erythroid cell lines have been instrumental in the pursuit of both pharmacological and genetic ways to reverse the postnatal hemoglobin switch. Here, we describe the first endogenously tagged fetal hemoglobin reporter cell line based on the adult erythroid progenitor cell line HUDEP2. Utilizing CRISPR-Cas9-mediated knock-in, a bioluminescent tag was integrated at the HBG1 gene. Subsequent extensive characterization confirmed that the resulting reporter cell line closely mirrors the HUDEP2 characteristics and that the cells report fetal hemoglobin induction with high sensitivity and specificity. This novel reporter cell line is therefore highly suitable for evaluating genetic and pharmacologic strategies to induce fetal hemoglobin. Furthermore, it provides an assay compatible with high-throughput drug screening, exemplified by the identification of a cluster of known fetal hemoglobin inducers in a pilot study. This new tool is made available to the research community, with the aspiration that it will accelerate the search for safer and more effective strategies to reverse the hemoglobin switch.

| S-EPMC11302795 | 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

Potent and uniform fetal hemoglobin induction via base editing

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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.

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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

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Fetal Hemoglobin Induction by Epigenetic Drugs.

Project description:Fetal hemoglobin (HbF) inhibits the root cause of sickle pathophysiology, sickle hemoglobin polymerization. Individuals who naturally express high levels of HbF beyond infancy thus receive some protection from sickle complications. To mimic this natural genetic experiment using drugs, one guiding observation was that HbF is increased during recovery of bone marrow from extreme stress. This led to evaluation and approval of the cytotoxic (cell killing) drug hydroxyurea to treat sickle cell disease. Cytotoxic approaches are limited in potency and sustainability, however, since they require hematopoietic reserves sufficient to repeatedly mount recoveries from stress that destroys their counterparts, and such reserves are finite. HbF induction even by stress ultimately involves chromatin remodeling of the gene for HbF (HBG), therefore, a logical alternative approach is to directly inhibit epigenetic enzymes that repress HBG-implicated enzymes include DNA methyltransferase 1, histone deacetylases, lysine demethylase 1, protein arginine methyltransferase 5, euchromatic histone lysine methyltransferase 2 and chromodomain helicase DNA-binding protein 4. Clinical proof-of-principle that this alternative, noncytotoxic approach can generate substantial HbF and total hemoglobin increases has already been generated. Thus, with continued careful attention to fundamental biological and pharmacologic considerations (reviewed herein), there is potential that rational, molecular-targeted, safe and highly potent disease-modifying therapy can be realized for patients with sickle cell disease, with the accessibility and cost-effective properties needed for world-wide effect.

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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.

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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

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