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

Abstract

Oxygen, which is necessary for sustaining energy metabolism, is consumed in many biochemical reactions in eukaryotes. When the oxygen supply is insufficient for maintaining multiple homeostatic states at the cellular level, cells are subjected to hypoxic stress. Hypoxia induces adaptive cellular responses mainly through hypoxia-inducible factors (HIFs), which are stabilized and modulate the transcription of various hypoxia-related genes. In addition, many epigenetic regulators, such as DNA methylation, histone modification, histone variants, and adenosine triphosphate-dependent chromatin remodeling factors, play key roles in gene expression. In particular, hypoxic stress influences the activity and gene expression of histone-modifying enzymes, which controls the posttranslational modification of HIFs and histones. This review covers how histone methylation and histone acetylation enzymes modify histone and nonhistone proteins under hypoxic conditions and surveys the impact of epigenetic modifications on gene expression. In addition, future directions in this area are discussed.

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

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.