lncRNA LINC-PINT controls lymphatic function and inflammatory profile in lymphedema.

Abstract

Lymphedema is a lymphatic dysfunction leading to an accumulation of fluid and fat in the arm or leg. Here, we performed noncoding RNA profiling of human breast cancer-induced secondary lymphedema. We identified the long intergenic non-protein coding RNA, P53-induced transcript (<i>LINC-PINT</i>), as essential for the lymphedema development. <i>LINC-PINT</i> is the most expressed lncRNA in human lymphatic endothelial cells (LECs) under stress condition. Knocking down <i>LINC-PINT</i> in LECs promotes the expression of inflammation-related genes. Mechanistically, ATAC-seq revealed that <i>LINC-PINT</i> induces the transcription of genes involved in lymphangiogenesis and immune cell adhesion by increasing chromatin accessibility. Notably, <i>LINC-PINT</i> deficiency impairs LEC proliferation, migration, and sprouting. Conditional deletion of <i>Lnc-Pint</i> in mouse lymphatic endothelium (Lnc-Pint^lecko) leads to a reduction in dermal lymphatic network density. Lnc-Pint^lecko mice exhibit decreased lymphedema, reduced dermal backflow, fibrosis, and inflammation. Our findings unveil a crucial molecular role of <i>LINC-PINT</i> in lymphatic function and hold substantial clinical implications for lncRNA as biomarker of lymphedema.