Abstract
Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determined, for the first time, the global lineage-specific lncRNAome of human dermal blood and lymphatic endothelial cells (BECs and LECs), combining RNA-Seq and CAGE-Seq. A subsequent genome-wide antisense oligonucleotide-knockdown screen of a robust set of BEC- and LEC-specific lncRNAs identified LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein, and phenotype rescue analyses revealed that LETR1 acts as a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides new evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* These two authors share co-senior authorship
The main changes from the previous version of the manuscript refer to our renaming of the four lncRNA candidates. After discussing with the HUGO consortium, we agreed to officially rename only LINC01197 as LETR1 (lymphatic endothelial transcriptional regulator lncRNA 1) and leave unchanged the other three candidates. Therefore, all the appropriate changes were made throughout the manuscript.