HIF1A recruits primate-specific endogenous retroviruses into the human hypoxic and immune responses

Oxygen levels fluctuate widely across the human body and intensify during inflammation, infection, tissue damage, and disease. Consequently, immune cells must constantly adjust their genetic activity and metabolic processes in response to varying oxygen availability. Hypoxia-inducible factor 1 (HIF1A) plays a crucial role in this adaptation, acting as a marker of cellular reactions to reduced oxygen supply.

However, most of the human genome has remained relatively unexamined due to previous studies focusing on a small, non-repetitive portion of the genetic material.

This study examines the landscape of gene and transposable-element (TE) activity related to the human hypoxic response across various tissues, cell lines, and conditions. The research reveals that TE responses play a significant role in hypoxic adaptation, which has been overlooked until now. When tested in transformed cells and primary immune cells derived from blood and the tonsil - a region of the body sensitive to oxygen levels - HIF1A-driven TE activation was observed.

Single-cell analysis of peripheral blood mononuclear cells (PBMC) under hypoxic conditions, HIF stabilization, and interferon stimulation showed that while gene responses were highly variable between cell types, TE responses were predominantly activated.

Furthermore, the study found that ~70-90% of tested TE families were induced under hypoxia, with the tonsil cells demonstrating a unique pattern of activity. Approximately 80% of HIF1A-bound LTR7 elements contained a hypoxia-response element, and disrupting HIF1A DNA binding significantly reduced the expression of occupied HERVH loci.

The researchers also discovered that CRISPR deletion of individual LTR7/HERVH loci altered the expression of distant and neighboring genes, indicating that hypoxia-responsive retroelements can actively participate in host gene regulation and contribute to overall physiology. The findings suggest that HIF1A recruits specific endogenous retroviral elements into the human hypoxic response, extending oxygen-dependent regulation beyond traditional gene promoters and providing an additional regulatory layer through which tissue oxygenation can influence immune-cell state and human physiology.