Fig. 2: Oxygen in development and HIF-1α regulation.

a The role of oxygen in development starts from embryonic development up to post-natal phase. Early hypoxic conditions trigger HIF1-a accumulation, thus targeting genes associated with vascularization (such as VEGF) to encourage organ formation and placental-fetus interactions. After the placenta is formed, oxygen levels rise up to 38 mmHg. b During normoxia, HIF-1a is regulated by prolyl hydroxylation. The HIF1-a subunits contain three sites for hydroxylation (two on prolyl residues within the oxygen-dependent degradation domain (ODDD) and one on an asparaginyl residue within the C-terminal transactivation domain (C-TAD)). Upon oxygen-dependent Fe(II)-, oxygen-, and 2-oxoglutarate, PHDs facilitate prolyl hydroxylation. This is then recognized by the von Hippel-Lindau protein (pVHL), which then marks it for degradation through a process called ubiquitination, leading to its breakdown by the proteasome. Separately, the asparaginyl hydroxylation process is driven by an enzyme called factor-inhibiting HIF (FIH) acting on a specific site in the C-TAD. In hypoxia, when the hydroxylation is suppressed or PHDs are inhibited, HIF-1a is translocated into the nucleus, where it heterodimerises with HIF1-b subunit allowing binding to hypoxia-response elements (HREs). Adapted from¹²⁴. Figure created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.