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Related Concept Videos

General Transcription Factors01:30

General Transcription Factors

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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

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Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
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Hypoxia01:23

Hypoxia

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Hypoxia is a medical condition characterized by an inadequate oxygen supply to body tissues. It typically manifests as a bluish discoloration of the skin and mucosae, especially in fair-skinned individuals, when hemoglobin (Hb) saturation drops below 75%.
Types of Hypoxia
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Transcription Factors02:16

Transcription Factors

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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Role of Hematopoietic Growth Factors01:28

Role of Hematopoietic Growth Factors

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Hematopoietic growth factors are molecules that regulate the differentiation rate of hematopoietic stem cells (HSCs). Erythropoietin (EPO), primarily produced by the kidneys, plays a crucial role in erythrocyte production. When oxygen levels in the blood are low, EPO is released into the bloodstream, reaching the bone marrow, where it stimulates HSCs to differentiate and mature into erythrocytes, which are vital for oxygen transport.
Thrombopoietin (TPO), mainly released by the liver,...
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Erythropoiesis01:14

Erythropoiesis

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Red blood cells  (RBCs) transport oxygen to all body tissues. These cells survive only for 120 days and then need to be replenished. Erythropoiesis is the process of RBC production. In healthy individuals, erythropoiesis ensures all tissues are amply supplied with oxygen. In addition, blood loss due to injury leads to a drop in the physiological oxygen level that will cause erythropoiesis. Any defect in erythropoiesis leads to several physiological disorders, including thalassemia, anemia,...
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Activation of γ-globin expression by hypoxia-inducible factor 1α.

Ruopeng Feng1, Thiyagaraj Mayuranathan1, Peng Huang2

  • 1Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, USA.

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|October 12, 2022
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Researchers identified a new way to boost fetal hemoglobin (HbF) production in red blood cells (RBCs) by targeting the VHL-HIF1α pathway. This discovery offers a potential therapeutic strategy for treating blood disorders like sickle cell disease and β-thalassemia.

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Area of Science:

  • Hematology
  • Molecular Biology
  • Genetics

Background:

  • Human red blood cells (RBCs) normally switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA) after birth.
  • This developmental shift is a key target for treating genetic blood disorders like sickle cell disease and β-thalassemia.

Purpose of the Study:

  • To identify novel regulators of globin gene switching and fetal hemoglobin (HbF) expression using a CRISPR-Cas9 screen.
  • To elucidate the molecular mechanisms underlying HbF induction in erythroid precursors.

Main Methods:

  • Conducted a CRISPR-Cas9 screen targeting ubiquitin-proteasome components to identify regulators of HbF.
  • Investigated the role of the von Hippel-Lindau (VHL) E3 ubiquitin ligase and hypoxia-inducible factor 1α (HIF1α) in γ-globin gene expression.
  • Analyzed gene regulation, chromatin interactions, and transcriptional activation in response to VHL depletion or hypoxia.

Main Results:

  • Depletion of VHL stabilized HIF1α, leading to increased γ-globin gene transcription and HbF production in RBC precursors.
  • HIF1α-HIF1β heterodimers were found to bind regulatory elements of the BGLT3 long noncoding RNA gene, influencing γ-globin gene expression.
  • HbF induction was also observed under hypoxic conditions or upon inhibition of prolyl hydroxylase domain enzymes, mimicking VHL-mediated stabilization of HIF1α.

Conclusions:

  • The study links globin gene regulation to canonical hypoxia adaptation pathways.
  • A novel mechanism for HbF induction during stress erythropoiesis involving the VHL-HIF1α axis was identified.
  • These findings suggest a promising new therapeutic avenue for β-hemoglobinopathies by modulating HbF levels.