Long non-coding RNA LINC00607 epigenetically regulates endothelial TSPAN18 to promote hypoxia-induced thromboinflammation

Abstract

Hypoxia promotes endothelial dysfunction and thrombosis through transcriptional and epigenetic mechanisms that remain incompletely understood. Long non-coding RNAs have emerged as important regulators of endothelial gene expression, yet their contribution to hypoxia-driven thromboinflammatory signaling is poorly defined. Here, we identified the endothelial-enriched long non-coding RNA LINC00607 as a hypoxia-inducible regulator linking chromatin remodeling to pro-thromboinflammatory endothelial activation. Integrative transcriptomic and chromatin analyses revealed that hypoxia upregulates LINC00607 and its downstream effector TSPAN18, a member of the tetraspanin superfamily of transmembrane proteins, accompanied by increased enhancer acetylation and chromatin accessibility under hypoxia. Loss- and gain-of-function experiments demonstrated that LINC00607 is required and sufficient for TSPAN18 induction. Mechanistically, LINC00607 associates with the chromatin remodeler BRG1 and facilitates BRG1-dependent activation of the TSPAN18 enhancer, while pharmacological inhibition of BRG1 attenuated this response. Functionally, the activation of LINC00607 -TSPAN18 axis enhanced store-operated calcium entry and endothelial-monocyte adhesion under hypoxic conditions, key processes underlying endothelial activation and thromboinflammation. Although the ETS transcription factor ERG contributed to enhancer maintenance, LINC00607-mediated regulation of TSPAN18, persisted independently of ERG under hypoxia. Collectively, these findings define a hypoxia responsive LINC00607-BRG1-TSPAN18 regulatory axis that integrates epigenetic remodeling with calcium-dependent endothelial activation, providing a new insight into the molecular basis of hypoxia-induced thromboinflammatory responses.

Keywords: LINC00607; TSPAN18; endothelial; epigenetic; hypoxia; long non-coding RNA; thrombosis.