# Molecular Analysis of Normal and Thalassemic DNA

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $442,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Our work is based on the premise that a detailed, mechanistic understanding of how fetal hemoglobin (HbF)
is shut off in adult erythroid cells will provide new opportunities to interfere with the process and reactivate
HbF for clinical benefit in patients with b-thalassemia and sickle cell disease. BCL11A, a transcription factor,
plays a central role in silencing of g-globin gene expression in development and in adult erythroid cells.
Human genetics and experiments in the laboratory indicate that partial reduction of BCL11A function (to
about 40% of normal level) would be therapeutic. While the genetic findings are compelling, relatively little is
understood regarding the precise mechanisms by which BCL11A represses g-globin gene expression. A
current model posits that BCL11A executes its function in large part through binding to the g-globin promoter
at a specific site (a distal TGACCA motif) and recruits the NuRD chromatin complex to achieve repression.
Key aspects of this model will be tested by focused experiments. First, novel methods for conditional
degradation of BCL11A protein in cells will be employed to develop a system in which repression or
activation of g-globin gene transcription can be followed in a step-by-step manner. Specific predictions of the
current model for BCL11A action will be tested by generation of targeted mutations of BCL11A or subunits
of the NuRD complex in an immortal adult human erythroid cell line (HUDEP-2 cells). Findings from these
experiments that support or challenge aspects of the current model will drive formulation of a more
sophisticated description of how BCL11A acts and identify points at which g-globin gene silencing may be
reversed. These studies are essential for creating new opportunities for targeted reactivation of HbF
expression with small molecules (drugs). Such novel therapeutic approaches are desperately needed to
address the existing and growing global health burden of the hemoglobin disorders.

## Key facts

- **NIH application ID:** 9968332
- **Project number:** 5R01HL032259-37
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** STUART H ORKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 1982-04-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968332

## Citation

> US National Institutes of Health, RePORTER application 9968332, Molecular Analysis of Normal and Thalassemic DNA (5R01HL032259-37). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9968332. Licensed CC0.

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