Extended Data Fig. 9: Model of the activation of γ-globin transcription by HIF1α in adult-type erythroid cells.
From: Activation of γ-globin expression by hypoxia-inducible factor 1α
At high oxygen levels, HIF1α is hydroxylated by proline hydroxylase domain (PHD) enzymes and targeted for degradation by the VHL E3 ubiquitin ligase complex (not shown). The transcriptionally silent BGLT3, HBE, and γ-globin (HBG1 and HBG2) genes interact via chromatin looping, whereas the upstream LCR enhancer interacts with the active adult β-globin gene (HBB) to drive its transcription. At low oxygen levels, PHD enzymes are inactive and HIF1α accumulates and heterodimerizes with HIF1β. The HIF heterodimers bind two tandem HRE elements in BGLT3, leading to the recruitment of the transcriptional activators P300 and GATA1 (not shown), the acquisition of local enhancer functions, and the induction of the BGLT3 long noncoding RNA transcript (not shown). Activated BGLT3 unlocks the interaction with HBE, redirects the LCR to the γ-globin genes, and activates their transcription. The solid arrows indicate mRNA transcription. Yellow indicates transcriptionally active genes.
