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AMPK-beta1 Activation Induces Fetal Hemoglobin

ABSTRACT: AMPK-beta1 Activation Induces Fetal Hemoglobin

PROVIDER: PRJNA929046 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23261372_1.fastq.gz	Fastqsanger.gz
	SRR23261372_2.fastq.gz	Fastqsanger.gz
	SRR23261373_1.fastq.gz	Fastqsanger.gz
	SRR23261373_2.fastq.gz	Fastqsanger.gz
	SRR23261374_1.fastq.gz	Fastqsanger.gz

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AMPK-beta1 Activation Induces Fetal Hemoglobin

Project description:Previous studies report that metformin triggers fetal hemoglobin (HbF) induction in human erythroid cells through indirect activation of the AMPK/FOXO3 pathway. Here we investigated the underlying mechanism of HbF induction by direct activation of AMPKβ1 in erythroid cells to understand their potential as safe medication for sickle cell disease (SCD). Single-cell RNA sequencing of human bone marrow cells determined that AMPKβ1 predominates in the erythroid lineage compared to AMPKβ2 and expression of AMPKβ1 is mostly restricted to this lineage. Novel selective AMPKβ1 activators greatly increased expression of HbF, activated markers of the noncanonical Nrf2 pathway (phosphorylated ULK1 and SQSTM1), and ultimately decreased sickling of SCD donor CD34+ cells under hypoxia. Confirmation of the noncanonical Nrf2 pathway in AMPKβ1 driven HbF induction was achieved by abolishing increased HbF using a potent and selective inhibitor for SQSTM1/Keap1 complex formation. Preclinical studies in Townes SCD mice treated with PF-06409577, a clinical candidate AMPKβ1 activator, confirmed increased HbF induction and non-canonical Nrf2 pathway activation in erythroid cells, associated with decreased reactive oxidative species in bone marrow and decreased chronic inflammation markers. Based on the narrow tissue expression of AMPKβ1, our study strongly supports AMPKβ1 activators as safe activators of Nrf2 driven HbF induction compared to direct inhibitors of ubiquitous Keap1. Activation of the AMPKβ1/Nrf2 noncanonical pathway may be a promising therapeutic approach for SCD patients.

2025-05-21 | GSE223925 | GEO

PGC-1α Agonism Induces Fetal Hemoglobin and Exerts Anti-Sickling Effects in Sickle Cell Disease

Project description:Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. However, pharmacologic induction of fetal hemoglobin sufficient to diminish clinical severity in sickle patients has been challenging. We recently found that up-regulation of PGC-1α can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecular compound SR-18292 increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells or β-YAC and sickle cell disease mice. Sickled red blood cells are significantly reduced and disease complications are alleviated in SR-18292-treated sickle mice. SR-18292, or agents in its class, could be a promising therapeutic for sickle cell disease.

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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.

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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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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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Cholesterol-Modified MIR29B Induces Fetal Hemoglobin via targeting DNMT3A in Townes Sickle Cell Mice

Project description:Cholesterol-Modified MIR29B Induces Fetal Hemoglobin via targeting DNMT3A in Townes Sickle Cell Mice

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

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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.

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