# Post-Transcriptional Regulatory Mechanisms of Fetal Hemoglobin Repression

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $33,743

## Abstract

Abstract: β-Hemoglobinopathies are among the most common inherited monogenic disorders, yet treatment
options remain limited. These disorders are defined by an inability to produce enough functional adult
hemoglobin and have a variety of severe health outcomes. One major therapeutic approach which has proven
successful is to raise the expression level of fetal hemoglobin, a gene typically repressed over time during the
first months after birth. However, treatment methods are severely impeded by a lack of mechanistic knowledge
regarding fetal hemoglobin repression and hemoglobin switching. In this work, I propose experiments to
investigate the post-transcriptional regulation of adult and fetal β-type globin transcripts. Post-transcriptional
regulation of γ-globin RNA has been observed at multiple levels. First, the biology of the Corfu deletion has
shown post-transcriptional silencing of γ-globin transcripts derived from the Corfu allele despite the fact that
new transcription of γ-globin is elevated from all Corfu deletion alleles. Additionally, it has been observed that
treatment of CD34+ cells with salubrinal enhances the translation of γ-globin without affecting the transcript
stability or localization of either HBB or HBG transcripts. Further, studies in reticulocytes which lack nuclei have
demonstrated the capacity of butyrate to have similar effects despite its known role as an inhibitor of histone
deacetylases. Finally, in a recent CRISPR screen to identify HbF repressors, 20/117 hit genes were associated
with RNA binding, processing, or decay. Here, I propose experiments to follow up on DDX6, the RNA-binding
protein recently identified in our laboratory as the most potent novel HbF repressor. While DDX6 is central to
several distinct stages of RNA processing and decay including its role as a P-body constituent and as part of
miRNA-mediated silencing, the role of DDX6 in repression of fetal hemoglobin remains largely unexplored. To
identify mechanisms through which DDX6 may influence fetal hemoglobin expression, I will perform DDX6
eCLIP to identify RNA targets of DDX6 which may be relevant to fetal hemoglobin repression. Given the role of
DDX6 as a P-body constitutent, I will assess the subcellular localization of DDX6 protein and globin transcripts
in adult and fetal erythroid models. Further, I aim to directly test the ability of known DDX6 interacting proteins
identified by HbF repressor screen to bind directly to γ-globin transcripts in the presence or absence of DDX6.
Finally, I will use anti-sense oligo methods to pull down native hemoglobin transcripts and profile the RNA-
binding proteins attached to each transcript. Gaining insight into the post-transcriptional regulation of fetal
hemoglobin and to the role of DDX6 in fetal hemoglobin repression has the potential to identify new targets for
therapeutic intervention for patients diagnosed with β-Hemoglobinopathies including β-Thalassemia and Sickle
Cell Disease.

## Key facts

- **NIH application ID:** 10019321
- **Project number:** 5F31DK122637-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Steven Coyne
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,743
- **Award type:** 5
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019321

## Citation

> US National Institutes of Health, RePORTER application 10019321, Post-Transcriptional Regulatory Mechanisms of Fetal Hemoglobin Repression (5F31DK122637-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10019321. Licensed CC0.

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