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December 8, 2025BloodOpen Access

Structure guided targeting of the GATAD2A-CHD4 interaction in the MBD2-NuRD complex results in high levels of HbF

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Authors

SSShengzhe ShangGGGordon D. Ginder

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Overview

Structural analysis of GATAD2A-CHD4 interaction suggests small molecules may enhance fetal hemoglobin in patients with SCD.

Key Points

  • To identify and target the GATAD2A-CHD4 interaction in the MBD2-NuRD complex to raise fetal hemoglobin levels in sickle cell disease and beta-thalassemia patients.
  • Employed AlphaFold3 for structural predictions of GATAD2A and CHD4 interaction
  • Utilized NanoBRET and isothermal calorimetry to confirm binding
  • Conducted immunoprecipitation and chromatin immunoprecipitation assays
  • Performed RNA seq analysis to evaluate gene expression changes
  • Applied prime editing to modify key amino acids in GATAD2A
  • Disruption of GATAD2A-CHD4 interaction led to increased fetal hemoglobin levels
  • Isothermal calorimetry confirmed tight binding between protein domains
  • Mutations in GATAD2A disrupted high-affinity binding to CHD4
  • Significant upregulation of HBG1 and HBG2 observed post-editing
  • Peptidomimetic drugs demonstrated potential to improve outcomes by targeting GATAD2A.

Cite This Study

Shang et al. (2025) studied this question.

synapsesocial.com/papers/69362f364fa91c937236d2f2https://doi.org/10.1182/blood-2025-731
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Targeted disruption of BCL11A ZnF4 enhances fetal hemoglobin in β-thalassemia and sickle cell disease: A druggable approach2025
  2. 2A genome-wide CRISPR activation screen identifies novel γ-globin regulators2025
  3. 3A new HDAC1/2 degrader increases HbF production in human CD34⁺ cells at non-cytotoxic, differentiation-preserving dose2025
  4. 4TADA1 plays a regulatory role in erythropoiesis and the expression of HBG.2025
  5. 5Silencing of BCL11A by disrupting enhancer-dependent epigenetic insulation2025 · 1 citations