Sirt1 Increases the Expression of Fetal Hemoglobin Genes in Human Adult and Cord Blood Erythroblasts

High HbF ameliorates the clinical manifestations of β hemoglobinopathies. We studied SIRT1, a NAD-dependent class III histone deacetylase, to see if it had a role in suppressing HBG expression. Unexpectedly, it was an inducer of HBG expression. Ectopic expression of SIRT1 in cord blood CD34⁺ cells increased HBG mRNA 4-fold and the g-globin protein level 2.5-fold. SIRT1 knockdown in cord blood CD34⁺ cells decreased HBG mRNA 8-fold and γ-globin protein level 5-fold compared. Small molecule SIRT1 inducers induced an increase in HBG mRNA, and HbF-cells. SIRT1 binds in the β-globin gene cluster locus control region (LCR) and HBG promoters, and promotes the looping of the LCR to HBG promoter, and increases the binding of  RNA polymerase 2  and H4K16Ac in the HBG promoter. SIRT1 suppressed the expression of the HBG suppressors BCL11A, KLF1, HDAC1 and HDAC2. SIRT1 did not change the proliferation of human erythroid progenitor cells or the expression of differentiation marker CD235a. SIRT1 is an activator of HBG transcription. Our data suggest that SIRT1 activates HBG expression through facilitating LCR looping to the HBG promoter, inhibiting the expression of transcriptional suppressors of HBG, and indirectly increasing histone acetylation in the HBG promoter. SIRT1 is a potential therapeutic target for γ-globin induction, and small molecule SIRT1 activators might serve as a lead compound for the development of new HbF inducers.