Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin gene expression postnatally remains undefined. We mapped γ-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce γ-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate γ-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing.

胎儿血红蛋白 (HPFH) 的遗传持久性通过抑制从 γ-珠蛋白 ( HBG1 / HBG2 ) 向 β-珠蛋白 ( HBB )的发育转变来改善 β-血红蛋白病） 基因表达。某些形式的 HPFH 与 γ-珠蛋白启动子变体相关，这些变体要么破坏转录抑制因子的结合基序，要么为转录激活因子创造新的基序。这些变体如何在出生后维持 γ-珠蛋白基因表达仍未确定。我们在具有不同 HPFH 变体的红细胞中功能性地绘制了 γ-珠蛋白启动子序列。破坏 BCL11A 阻遏物结合元件的那些通过促进核转录因子 Y (NF-Y) 募集到附近的近端 CCAAT 盒和 GATA1 募集到上游基序来诱导 γ-珠蛋白表达。对于为激活剂 NF-Y 或 KLF1 生成新的结合基序的 HPFH 变体，近端 CCAAT 元件变得可有可无，但 GATA1 募集仍然必不可少。顺式调节元件在不同形式的 HPFH 中激活 γ-珠蛋白表达，其中一些是通过治疗性基因组编辑重建的。