Abstract
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.
Highlights
The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life
We have previously shown that all sequences required to produce fully regulated expression of the mouse and human ζ- and αglobin genes are contained within a ~65 kb sub-topologically associating domain (TAD) (Fig. 1 and refs. 16,17)
The cis-elements within this region, which are active in definitive erythropoiesis, have been previously identified by ATAC-seq and characterized by ChIP-seq to establish their chromatin signatures[12,19,20]
Summary
The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. We have examined the earliest developmental changes in globin gene expression which occur during the transition between embryonic and fetal life In both mice and humans, erythropoiesis occurs in distinct waves[5,6]. A cohort of cells originating in the embryonic yolk sac is released into the circulation as the heart begins to beat This cohort of primitive erythroid cells matures in a semi-synchronous manner and eventually the cells enucleate. On the basis of work in mice, there appears to be a second, transient wave of hematopoiesis, originating in the yolk sac, which migrates to the fetal liver and produces both erythroid and myeloid cells[7]. Cells arising from the splanchnopleura migrate to the floor of the dorsal aorta, where they undergo a transition to definitive hematopoietic stem cells that subsequently contribute to the formation of red blood cells throughout life[8]
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