Bringing Genetics and Epigenetics to the Fetal-Adult Hemoglobin Switch
Air date: Wednesday, January 21, 2015, 3:00:00 PM
Category: WALS – Wednesday Afternoon Lectures
Description: Wednesday Afternoon Lecture Series
During ontogeny the expression of genes encoding the beta-like globins in humans switches from embryonic, to fetal, to adult globins. The switch from fetal hemoglobin (HbF, alpha2 gamma2) to adult hemoglobin (HbA, alpha2 beta2) is critical to the beta-hemoglobin disorders, namely sickle-cell disease (SCD) and thalassemia. Family and natural-history studies have revealed the beneficial effects of increased HbF on the severity of these disorders. Thus, reactivation of HbF in adults has been a long-sought goal as a means to treat both SCD and beta-thalassemia. Until recently, the molecular basis of the HbF to HbA switch has been obscure.
This lecture will review recent findings that implicate the transcriptional repressor BCL11A as a principal regulator of the switch. The studies to be reviewed include genome-wide association studies, mouse genetics, biochemistry, and recent human genetics. Importantly, genetic variation in an essential erythroid enhancer within the BCL11A locus controls its output and now represents a prime candidate for genome editing as a novel form of gene therapy for the hemoglobin disorders. Ultimately, the discovery and development of small molecules that impair BCL11A function may provide a new class of drugs to treat these major diseases.
Author: Stuart H. Orkin, M.D., Chairman of the Department of Pediatric Oncology, Dana Farber Cancer Institute; Professor of Pediatric Medicine, Harvard Medical School; Investigator, Howard Hughes Medical Institute
Permanent link: http://videocast.nih.gov/launch.asp?18806