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

## TL;DR

This study identifies a long non-coding RNA that promotes blood clotting and inflammation in low oxygen conditions by regulating a specific protein in blood vessel cells.

## Contribution

The study reveals a novel epigenetic regulatory axis involving LINC00607, BRG1, and TSPAN18 in hypoxia-induced thromboinflammation.

## Key findings

- LINC00607 is a hypoxia-inducible RNA that enhances TSPAN18 expression through chromatin remodeling.
- The LINC00607–TSPAN18 axis promotes endothelial activation and monocyte adhesion under hypoxia.
- BRG1-dependent chromatin remodeling is essential for TSPAN18 activation by LINC00607.

## 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.