# MicroRNA-based epigenetic approach to induce fetal hemoglobin

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $318,302

## Abstract

Project Abstract
This SHINE II application seeks to explore epigenetic mechanisms that control globin gene
regulation during erythropoiesis. The central hypothesis of this project is that that miR-29b
reverses the γ-globin to β-globin gene switch and induces HbF via modulation of DNA
methylation. Therapeutic interventions aimed at inducing HbF expression is an effective approach
for ameliorating the clinical symptoms of sickle cell disease (SCD) in adults and children.
Hydroxyurea is the only FDA-approved drug with proven efficacy for inducing HbF in patients with
SCD, but DNA methyltransferase (DNMT) inhibitors have shown promise as HbF inducers by
producing proximal γ-globin promoter DNA hypomethylation. However, DNMT inhibitors can
produce off-target side effects. Small non-coding microRNAs (miR) are attractive molecules for
targeting repressors of γ-globin gene expression and studies show that miR-29b inhibits DNA
methylation through direct targeting of the 3’ untranslated region of DNMT3A and DNMT3B. The
objective of this proposal is to test the efficacy of miR-29b as an HbF inducer. Our published work
shows that miR-29b is important for reactivating γ-globin transcription and HbF expression by
targeting MYB, a known repressor of γ-globin involved in mediating DNA methylation and gene
silencing. To test our central hypothesis, we will accomplish one specific aim to determine the
ability of miR-29b to mediate epigenetic changes in DNA methylation in the HBB locus and
reactivate γ-globin transcription and HbF expression during adult erythropoiesis. Sub-aim A will
explore the molecular effects of miR-29b on γ-globin regulation using an in vitro primary liquid
culture system to generate erythroid progenitors from peripheral blood mononuclear cells isolated
from individuals with SCD. These findings will compare to normal erythroid progenitors to validate
the ability of miR-29b to reactivate γ-globin transcription through proximal promoter DNA
methylation. Off-target effects mediated by miR-29b will be investigated by DNA mutation and
RNA-seq analyses. To define the role of miR-29b in reversing phenotype, erythroid progenitor
sickling under hypoxic conditions will be evaluated. Sub-aim B will establish the optimal dose of
miR-29b that mediates γ-globin reactivation and HbF induction in vivo using a preclinical Townes
SCD mouse model. This research highlights a novel miRNA-based epigenetic approach to induce
HbF to impact the discovery of new drugs to expand treatment options for SCD.

## Key facts

- **NIH application ID:** 10049011
- **Project number:** 1R01HL144641-01A1
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Athena Starlard-Davenport
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $318,302
- **Award type:** 1
- **Project period:** 2020-07-13 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049011

## Citation

> US National Institutes of Health, RePORTER application 10049011, MicroRNA-based epigenetic approach to induce fetal hemoglobin (1R01HL144641-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10049011. Licensed CC0.

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