# Project 1 BCL11A Protein in Hemoglobin Regulation, Stuart H. Orkin

> **NIH NIH P01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $430,810

## Abstract

Abstract
The hemoglobin switch -- repression of γ-globin and activation of β-globin expression during the transition
from fetal to adult stages of erythropoiesis -- is a major paradigm for cell and developmental stage specific
regulation. Given family and genetic studies demonstrating the beneficial effects of increased HbF (α2γ2) in
the β-hemoglobin disorders -- sickle cell disease (SCD) and β-thalassemia -- efforts have been directed
towards manipulating the switch as a therapeutic approach. A major obstacle, however, has been ignorance
regarding how the switch is achieved and γ-globin silencing is maintained in the adult. Work in our group
over the past several years has established the repressor protein BCL11A as a central, quantitative
regulator of the switch. Moreover, critical sequences in an erythroid-specific enhancer within the BCL11A
gene are required for its expression, providing a target site for gene editing as an improved form of gene
therapy for patients with β-hemoglobin disorders. The remaining challenge now is development of
therapeutic strategies based on modulation of BCL11A function with small molecules, as a means to bring
mechanism-based therapy to wider populations. In this project we will focus on the BCL11A protein and
address three aspects. First, following our identification of components of the nuclear matrix in association
with BCL11A protein complexes, we will dissect the functional relationship between chromatin and the
nuclear matrix in erythroid cells. Second, with the goal of reducing the level of BCL11A protein and relieving
HbF repression, we will employ genetic and small molecule screens to test the possibility that inhibition of
deubiquitylases might constitute a new therapeutic approach to HbF reactivation. Third, we will perform
saturating CRISPR/Cas9 mutagenesis of the human Aγ−δ intergenic region to localize sequences required
for full HbF repression, and correlate these with chromatin sites proposed to bind BCL11A. In this manner,
we will identify critical cis-acting sequences bound by BCL11A, ascertain whether these are sites of
chromatin-nuclear matrix interaction, and define additional DNA sequences for therapeutic genome editing.
The goal of this project is to capitalize on our discovery of BCL11A as a major regulator of the hemoglobin
switch and develop innovative, and non-traditional, therapeutic approaches to the hemoglobin disorders.

## Key facts

- **NIH application ID:** 10146448
- **Project number:** 5P01HL032262-39
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** STUART H ORKIN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $430,810
- **Award type:** 5
- **Project period:** 1997-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146448

## Citation

> US National Institutes of Health, RePORTER application 10146448, Project 1 BCL11A Protein in Hemoglobin Regulation, Stuart H. Orkin (5P01HL032262-39). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10146448. Licensed CC0.

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