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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

Disrupting GATAD2A-CHD4 interaction enhances fetal hemoglobin in sickle cell disease, suggesting new therapeutic pathways.

Key Points

  • This research aims to identify targets for increasing fetal hemoglobin levels to improve outcomes in sickle cell disease.
  • Investigated GATAD2A-CHD4 interaction using AlphaFold3 for structural predictions.
  • Conducted NanoBRET and isothermal calorimetry assays to assess protein binding.
  • Applied genetic editing to mutate key amino acids in GATAD2A.
  • Performed chromatin immunoprecipitation and RNA seq analyses to measure changes in HBG expression.
  • Mutation of GATAD2A critical amino acids disrupted binding to CHD4.
  • High levels of fetal hemoglobin were achieved by editing GATAD2A.
  • Chromatin immunoprecipitation showed decreased occupancy of CHD4 at the HBG promoter.

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. 1Removal of promoter CpG methylation by epigenome editing reverses HBG silencing2025 · 12 citations
  2. 2Targeted disruption of BCL11A ZnF4 enhances fetal hemoglobin in β-thalassemia and sickle cell disease: A druggable approach2025
  3. 3Optimized CRISPR-Cas12a genome-wide screen reveals PTPA phosphatase pathway in fetal hemoglobin silencing2026 · 2 citations
  4. 4Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease2024
  5. 5A genome-wide CRISPR activation screen identifies novel γ-globin regulators2025