More than 40 years ago, scientists noticed that adding chemical tags called CpG methylation to DNA near certain genes kept them silent. They found that this tagging happens at the HBG gene promoters, switching off…
Scientists Solve Fetal Hemoglobin to Treat Blood Disorders
Gene silencing plays a big role in many diseases. Recently, scientists made exciting progress that could help people with β-hemoglobinopathies, serious blood disorders caused by faulty adult hemoglobin genes. This new discovery focuses on the fetal hemoglobin gene (HBG), which usually gets turned off after birth but can replace defective adult hemoglobin when reactivated.
The Mystery of Fetal Hemoglobin Silencing
More than 40 years ago, scientists noticed that adding chemical tags called CpG methylation to DNA near certain genes kept them silent. They found that this tagging happens at the HBG gene promoters, switching off the fetal hemoglobin genes. However, it wasn’t clear if these tags simply showed gene silencing or actually caused it.
This question sparked many research studies because if scientists could remove those tags, they might turn the HBG gene back on. This could increase fetal hemoglobin production and help treat diseases like sickle cell anemia or beta-thalassemia that affect adult hemoglobin.
The Role of UHRF1 in Gene Silencing
A recent study used a technique called CRISPR/Cas9 screening to search for proteins responsible for silencing HBG. The researchers found that a protein named UHRF1 is crucial in keeping the methylation marks during DNA copying.
UHRF1 recruits enzymes like DNMT1 to maintain CpG methylation on newly copied DNA strands. If UHRF1 is removed, these methyl marks fade away and HBG genes switch back on, producing fetal hemoglobin again.
Laboratory Proof Using Human Cells
Using cultured human erythroid cells (cells that produce red blood cells), scientists blocked UHRF1’s function. As a result, they observed significant activation of fetal hemoglobin genes and a drop in DNA methylation around these genes. Specifically, they showed 34% of the promoter regions lost all six key CpG methylations after UHRF1 disruption.
They also confirmed this effect in stem cell-derived red blood cell precursors from human donors, making it clear this mechanism works beyond just lab-grown cell lines.
The Epigenetic Switch: How Gene Expression Changes
Methylation and Chromatin Accessibility
Methylation marks act like stop signs for gene activity. In normal cells, high CpG methylation keeps HBG promoters tightly packed with proteins so transcription factors cannot access them easily.
Scientists found when UHRF1 was removed, chromatin became more open and accessible near HBG promoters. They saw increased binding of activators like GATA1 and NF-Y to these sites as well as histone modifications linked with active transcription (e.g., H3K4me3). This openness allows cellular machinery to read fetal hemoglobin instructions again.
A Reversible Process That Offers Hope
This work revealed an important detail: restoring these methyl marks reversed the gene activation effects. Researchers used specialized epigenome-editing tools to add back DNA methyl groups at HBG promoters and silenced fetal hemoglobin once more.
This reversibility means treatment targeting UHRF1 or its pathway could dynamically control abnormal gene expression without permanent genetic damage.
Toward Future Therapies for Blood Diseases
This exciting research shines light on how epigenetic regulation controls essential human genes involved in blood formation. Understanding UHRF1’s function creates new treatment avenues focused on controlling CpG methylation rather than altering DNA sequences directly.
The next steps include developing drugs or delivery systems that can safely inhibit UHRF1 activity temporarily in patient red blood cell progenitors to boost fetal hemoglobin levels therapeutically.
A major benefit is offering hope for those suffering from sickle cell disease and other β-globin disorders without needing risky bone marrow transplants or expensive lifelong treatments.
Additionally, to stay updated with the latest developments in STEM research, visit ENTECH Online. Basically, this is our digital magazine for science, technology, engineering, and mathematics. Further, at ENTECH Online, you’ll find a wealth of information.
Reference
Bell, H. W., Feng, R., Shah, M., Yao, Y., Douglas, J., Doerfler, P. A., Mayuranathan, T., O’Dea, M. F., Li, Y., Wang, Y., Zhang, J., Mackay, J. P., Cheng, Y., Quinlan, K. G. R., Weiss, M. J., & Crossley, M. (2025). Removal of promoter CpG methylation by epigenome editing reverses HBG silencing. Nature Communications, 16(1), 6919. https://doi.org/10.1038/s41467-025-62177-z
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I’m a web developer and science writer with a Master’s degree in Computer Applications (MCA) from Pune University.
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