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 (LINC-PINT), as essential for the lymphedema development. LINC-PINT is the most expressed lncRNA in human lymphatic endothelial cells (LECs) under stress condition. Knocking down LINC-PINT in LECs promotes the expression of inflammation-related genes. Mechanistically, ATAC-seq revealed that LINC-PINT induces the transcription of genes involved in lymphangiogenesis and immune cell adhesion by increasing chromatin accessibility. Notably, LINC-PINT deficiency impairs LEC proliferation, migration, and sprouting. Conditional deletion of Lnc-Pint in mouse lymphatic endothelium (Lnc-Pintlecko) leads to a reduction in dermal lymphatic network density. Lnc-Pintlecko mice exhibit decreased lymphedema, reduced dermal backflow, fibrosis, and inflammation. Our findings unveil a crucial molecular role of LINC-PINT in lymphatic function and hold substantial clinical implications for lncRNA as biomarker of lymphedema.