Gamma-globin induction for beta-hemoglobinopathies

The National Heart, Lung, and Blood Institute awarded Regents of the University of Michigan $104,608 under the Cardiovascular Diseases Research program (CFDA 93.837) on December 16, 2026, as a Project Grant (F30HL180048).

The award funds research to determine the mechanisms by which TADA2B and SKIL regulate gamma-globin expression, with the goal of developing new therapeutic approaches for beta-hemoglobinopathies including sickle cell disease and beta-thalassemia. Preliminary genome-scale CRISPR knockout and activation screens identified TADA2B, a component of the SAGA transcriptional regulatory complex, and SKIL, a regulator of TGF-beta signaling, as candidate modulators of gamma-globin production. The research will characterize how perturbation of these genes leads to increased fetal hemoglobin production, which reduces clinical severity in beta-hemoglobinopathies when reactivated.

Performance runs through September 30, 2029, with work performed in Ann Arbor, Michigan. The University of Michigan, operating through its Office of Research and Sponsored Projects Division, is the recipient. This award is a component of NHLBI's broader program supporting heart, lung, and blood disease research across basic, translational, clinical, and population sciences.

Abstract

My long-term goal as a physician scientist is to contribute to our understanding of normal and abnormal hematopoiesis and translate these findings into new treatments for patients with hematologic conditions. Β- hemoglobinopathies are the most common monogenic disorders in the world. They include sickle cell disease (SCD) and β-thalassemia (β-thal), which are caused by defective or inadequate production of β-globin, respectively. Current treatment options for these disorders have limited efficacy or remain inaccessible to most patients. Reactivation of γ-globin, the β-like globin chain expressed during fetal development, results in production of fetal hemoglobin (HBF) and reduces the clinical severity of SCD and β-thalassemia. Identification of novel regulators of γ-globin could lead to the development of new therapies. In preliminary studies, we performed a genome-scale crispr knockout screen to identify novel γ-globin repressors. This screen identified several genes in the SPT-ADA-GCN5-acetyltransferase (saga) transcriptional regulatory complex as candidate γ-globin repressors, including the transcriptional adaptor protein TADA2B. Genetic perturbation of TADA2B results in a profound increase in γ-globin protein levels mediated at the transcriptional level. TADA2B is required for full activity of the saga complex acetyltransferases KAT2A and KAT2B, and pharmacologic protein degradation of KAT2A/b led to robust induction of γ-globin. In parallel, we performed a genome-scale crispr activation screen for genes that positively regulate γ-globin production. Screening identified skil, a regulator of TGF-β signaling, as an enhancer of γ-globin expression. Overexpression of skil resulted in increased γ-globin protein production mediated at the transcriptional level. The aim of this project is to determine the mechanism by which (1) TADA2B and (2) skil regulate γ-globin expression. This will be accomplished through targeted genetic and pharmacologic studies in established in vitro and in vivo models of normal human erythropoiesis and SCD. Results obtained from this proposal will enhance our understanding of γ-globin regulation, which may lead to improved treatments for β-hemoglobinopathies. The research and training plan will be supported by the excellent research and clinical environment at the university of michigan and will facilitate my development into an independent physician scientist focused on hematopoietic disorders.