Reactivation of a developmentally silenced embryonic globin gene.
King AJ., Songdej D., Downes DJ., Beagrie RA., Liu S., Buckley M., Hua P., Suciu MC., Marieke Oudelaar A., Hanssen LLP., Jeziorska D., Roberts N., Carpenter SJ., Francis H., Telenius J., Olijnik A-A., Sharpe JA., Sloane-Stanley J., Eglinton J., Kassouf MT., Orkin SH., Pennacchio LA., Davies JOJ., Hughes JR., Higgs DR., Babbs C.
The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.