Fig. 1: Mechanisms of hypoxic gene expression in the context of chromatin structure. | Experimental & Molecular Medicine

Fig. 1: Mechanisms of hypoxic gene expression in the context of chromatin structure.

From: Gene regulation by histone-modifying enzymes under hypoxic conditions: a focus on histone methylation and acetylation

Fig. 1

a In normoxia, HIFα is subjected to oxygen-dependent prolyl hydroxylation via PHDs, leading to its proteasomal degradation. FIH inhibits HIFα signaling by hydroxylating an asparagine residue in HIFα and dissociating the HIFα–p300 complex. Under hypoxic stress, HIFα is stabilized mainly via the inactivation of PHDs and FIH. It then translocates to the nucleus to form a heterodimer with HIFβ, which binds to hypoxia response elements (HREs), increasing gene transcription. The stability and transactivity of HIFα are further modulated by its acetylation and methylation. Under hypoxic conditions, histone-modifying enzymes dynamically change the chromatin structure. Some HMTs (e.g., G9a and EZH2) and HDACs form heterochromatin by inducing repressive histone marks. In contrast, other HMTs (e.g., MLL1 and SETD1B), HDMs (e.g., LSD1, KDM3A, KDM4A-C, KDM6A, and KDM6B), and HATs (e.g., p300/CBP and TIP60) induce activating marks in chromatin, forming euchromatin. These events lead to the activation of hypoxia-related genes, including those associated with glycolysis, angiogenesis, and autophagy. b Some JMJC histone demethylases (e.g., KDM4A, KDM4B, KDM5A, KDM6A, and KDM6B) function as direct oxygen sensors. Enzymatic inactivation has been observed under specific hypoxic conditions and induces the formation of either heterochromatin or euchromatin.

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