Chemical and genomic identification of globin regulators that induce fetal hemoglobin reactivation

Recorded On: 02/07/2018

Red blood cell disorders like Sickle Cell Disease (SCD) and beta-thalassemias are caused by alterations within the gene for the hemoglobin beta (HBbeta) subunit. A fetal ortholog of HBbeta, hemoglobin gamma (HBgamma) can reverse disease-related pathophysiology in these disorders by also forming complexes with the required hemoglobin alpha subunit. Because beta-like globin expression is developmentally regulated, with a reduction in the fetal ortholog (gamma) occurring shortly after birth concomitantly with an increase in the adult ortholog (beta), it has been postulated that maintaining expression of the anti-sickling gamma ortholog may be of therapeutic benefit in children and adults. Previously, inhibitors of chromatin modifying enzyme G9a/GLP (G9a-i) have been shown to upregulate HBgamma expression relative to HBbeta expression and therefore G9a/GLP has been proposed as a reasonable molecular target for maintenance of the anti-sickling HBgamma ortholog.  However, we have uncovered limitations to G9a-i as a therapeutic strategy to reactivate HBgamma and therefore set out to identify novel modulators and targets of HBgamma expression using both chemical probe and CRISPR-based genetic screening strategies.  We identified multiple druggable components of lipid metabolism, nuclear receptor pathways and transcription/chromatin regulatory pathways that modulate HBgamma mRNA using our automated, cell-based chemical genetic screening platform. Through characterization of these regulators, we have demonstrated that CRISPR targeting of different protein domains of components of the globin regulatory network can have profoundly different effects on globin gene expression patterns.  More specifically, modulation of key domains of chromatin writers, readers and erasers results in markedly different globin expression profiles that informs small molecule discovery against these novel targets. Additionally, we are utilizing a newly developed in vitro SCD cellular model to investigate how these globin gene regulators impact SCD pathophysiology.

Pete Rahl

Fulcrum Therapeutics

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