Hypoxia induces rapid changes to histone methylation and reprograms chromatin

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Oxygen is vital for multicellular life, with enzymes like molecular dioxygenases utilizing it.
• Histone demethylase enzymes, containing a Jumanji-C (JmjC) domain, are a subclass of dioxygenases.
• Hypoxia's effects on chromatin are known, but the direct role of JmjC-histone demethylases remains unclear.

Purpose of the Study:

• To investigate the direct impact of hypoxia on JmjC-histone demethylases.
• To determine if hypoxia directly alters histone methylation.
• To elucidate the mechanism of oxygen sensing by chromatin.

Main Methods:

• Utilized human cultured cells exposed to hypoxic conditions.
• Monitored histone methylation, specifically histone-3 lysine-4 trimethylation (H3K4me3) and H3K36me3.
• Inactivated the JmjC-containing enzyme lysine demethylase 5A (KDM5A) to observe cellular responses.

Main Results:

• Hypoxia induces rapid, hypoxia-inducible factor-independent histone methylation.
• Specific histone methylation marks (H3K4me3, H3K36me3) predict subsequent transcriptional changes.
• KDM5A inactivation effectively mimics hypoxia-induced cellular responses.

Conclusions:

• Chromatin directly senses oxygen levels through the inhibition of JmjC-histone demethylases.
• JmjC-histone demethylase activity is crucial for responding to hypoxic conditions.
• This study uncovers a novel epigenetic mechanism for oxygen sensing in cells.