Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A

Abstract

Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the β-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high-HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the β-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in β-hemoglobin disorders.

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

“…However, KLF1 inhibits γ-globin expression by transactivating BCL11A. 23 In the present reporter assays in K-562 cells, the transcriptional activities of the γ-globin promoter were unaffected, because these cells do not express BCL11A. High levels of zinc protoporphyrin were present only in compound heterozygotes with two KLF1 mutations in trans, as previously described in a Sardinian HPFH family, 13 although the combination of mutations in this study differed from the Sardinian variants c.809C4A (p. (Ser270Ter)) and c.994A4C (p.(Lys332Gln)).…”

Human genetics: Hit or miss?

“…Stuart Orkin's lab at Harvard Medical School in Boston reduced expression of BCL11A in cultured blood progenitor cells from humans. Fetal haemoglobin expression went up, suggesting that the gene normally acts as a repressor 3 . In a follow-up study 4 , the group showed that the gene controls the silencing of fetal haemoglobin during development in mice.…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…We were able to demonstrate that BCL11A is a potent silencer of HbF in human adult erythroid cells and has a key role in developmental hemoglobin switching (35,36). BCL11A appears to associate with key corepressor complexes and mediate chromatin looping (37,38), although the exact mechanisms by which it is able to silence the HbF genes remain unknown.…”