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Control of hemoglobin expression by the chromatin remodeler CHD7

Award Number: R03DK147724
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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Control of hemoglobin expression by the chromatin remodeler CHD7 - PROJECT SUMMARY / ABSTRACT The developmental switch from fetal (HbF) to adult (HbA) hemoglobin expression is important scientifically as a paradigm of developmental transcriptional control and clinically as a target for treatment of hemoglobinopathies. Reversing this switch to increase HbF expression is an essential approach for gene therapy and new small molecule therapeutics to treat sickle cell disease and b-thalassemia. BCL11A, expressed exclusively in adult cells, is the predominant transcriptional repressor of HbF. However, attempts to develop specific small molecule BCL11A modulators have not been successful, leading to a concerted effort to understand the developmental regulation of BCL11A itself to uncover basic principles of developmental globin control and identify more amenable targets. We used two converging approaches to identify the CHARGE- syndrome associated chromatin remodeler CHD7 as a specific HbF regulator. First, CHD7 scored as an HbF activator in a CRISPR screen of chromatin remodeling proteins. Independently, we found that CHD7 is expressed at higher levels in a small subset of adult erythroblasts that can turn on HbF either spontaneously or in response to pharmacological inducers. In preliminary experiments, we find that CHD7 is expressed predominantly in fetal cells, but that ablation of residual CHD7 in adult erythroblasts leads to transcriptional upregulation of BCL11A and repression of HbF. We hypothesize that CHD7 is a developmentally controlled activator of HbF expression through BCL11A and potentially through direct action at the b-globin gene locus. In Aim 1, we will determine the mechanisms of CHD7 gene selectivity in globin gene regulation. In Aim 2, we will characterize the developmental control of CHD7 expression. This dissection of CHD7’s regulation and selectivity may provide new opportunities to therapeutically manipulate fetal hemoglobin for the treatment of sickle cell disease (SCD) and b-thalassemias. Additionally, we will use the extensive tools and data sets developed in erythroid cells to better understand the activity of CHD7 in other biological contexts.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $133,500 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/7/2026	NEW	$133,500
														Subtotal = $133,500

Grand Total All Awards = $133,500

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Control of hemoglobin expression by the chromatin remodeler CHD7

Award Number: R03DK147724

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/05/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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