Hypoxia-induced downregulation of RNA m6A protein machinery in the naked mole-rat heart

Naked mole-rats, Heterocephalus glaber, are champion hypoxia-tolerant rodents that live under low oxygen conditions in their subterranean burrows. Detrimental effects of low oxygen can be mitigated through metabolic rate depression (MRD), metabolic reorganization, and global downregulation of nonessential cellular processes. Recent research has progressively implicated epigenetic modifications – rapid, reversible changes to gene expression that do not alter the DNA sequence itself – as major players in implementing and maintaining MRD. N⁶-adenosine (m⁶A) methylation is the most prevalent mammalian RNA modification and is responsible for pre-mRNA processing and mRNA export from the nucleus. Hence, m⁶A -mediated conformational changes alter the cellular fate of transcripts. The present study investigated the role of m⁶A RNA methylation responses to 24 h of hypoxia exposure in H. glaber cardiac tissue. Total protein levels of m⁶A writers/readers/erasers, m⁶A demethylase activity, and total m⁶A quantification were measured under normoxic vs. hypoxic conditions in H. glaber heart. While there was no change in either demethylase activity or total m⁶A content, many proteins of the m⁶A pathway were downregulated during hypoxia. Overall, m⁶A may not be a signature hypoxia-responsive characteristic in H. glaber heart, but downregulation of the protein machinery involved in m⁶A cycling points to an alternate biological involvement. Further research will explore other forms of RNA modifications and other epigenetic mechanisms to determine the controls on hypoxia endurance in this subterranean mammal.