Activation of g-globin expression by hypoxia-inducible factor 1a [CUT&RUN]
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ABSTRACT:
PROVIDER: PRJNA842691 | ENA |
REPOSITORIES: ENA
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Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
2022-07-14 | GSE204900 | GEO
Project description:Chromosomal loop engineering in human beta globin locus (CUT & RUN)
| PRJNA673302 | ENA
Project description:BCL11A, the major regulator of HbF(α2γ2) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult adult-type HbA (α2β2) production. Yet, the mechanism remains unclear. To uncover how BCL11A initiates repression, we used CRISPR/Cas9 and dCas9 screens to dissect the γ-globin promoters and identified an apparent activator element near the BCL11A binding region. Using CUT&RUN and base editing approaches, we demonstrate that this element, the proximal CCAAT box, is the binding site of transcription activator NF-Y. BCL11A competes with NF-Y binding through steric hindrance to initiate γ-globin repression, and the distance between the two motifs is critical for direct competition. Occupancy of NF-Y is rapidly established upon BCL11A depletion, and precedes γ-globin derepression and LCR-globin loop formation. Our findings reveal that the critical fetal-to-adult hemoglobin switch is initiated by the competition between transcription factors within a discrete region in the γ-globin promoters.
2020-12-22 | GSE150529 | GEO
Project description:Activation of g-globin expression by hypoxia-inducible factor 1a
| PRJNA764707 | ENA
Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
2022-07-14 | GSE204899 | GEO
Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
2022-07-14 | GSE204897 | GEO
Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
2022-07-14 | GSE184459 | GEO
Project description:Activation of g-globin expression by hypoxia-inducible factor 1a [CaptureC]
| PRJNA842692 | ENA
Project description:Activation of g-globin expression by hypoxia-inducible factor 1a [ATAC-Seq]
| PRJNA842682 | ENA