Long noncoding RNA LISPR1 is required for S1P signaling and endothelial cell function

J Mol Cell Cardiol. 2018 Mar;116:57-68. doi: 10.1016/j.yjmcc.2018.01.015. Epub 2018 Feb 3.

Abstract

Sphingosine-1-Phosphate (S1P) is a potent signaling lipid. The effects of S1P are mediated by the five S1P receptors (S1PR). In the endothelium S1PR1 is the predominant receptor and thus S1PR1 abundance limits S1P signaling. Recently, lncRNAs were identified as a novel class of molecules regulating gene expression. Interestingly, the lncRNA NONHSAT004848 (LISPR1, Long intergenic noncoding RNA antisense to S1PR1), is closely positioned to the S1P1 receptors gene and in part shares its promoter region. We hypothesize that LISPR1 controls endothelial S1PR1 expression and thus S1P-induced signaling in endothelial cells. In vitro transcription and translation as well as coding potential assessment showed that LISPR1 is indeed noncoding. LISPR1 was localized in both cytoplasm and nucleus and harbored a PolyA tail at the 3'end. In human umbilical vein endothelial cells, as well as human lung tissue, qRT-PCR and RNA-Seq revealed high expression of LISPR1. S1PR1 and LISPR1 were downregulated in human pulmonary diseases such as COPD. LISPR1 but also S1PR1 were induced by inflammation, shear stress and statins. Knockdown of LISPR1 attenuated endothelial S1P-induced migration and spheroid outgrowth of endothelial cells. LISPR1 knockdown decreased S1PR1 expression, which was paralleled by an increase of the binding of the transcriptional repressor ZNF354C to the S1PR1 promoter and a reduction of the recruitment of RNA Polymerase II to the S1PR1 5'end. This resulted in attenuated S1PR1 expression and attenuated S1P downstream signaling. Collectively, the disease relevant lncRNA LISPR1 acts as a novel regulatory unit important for S1PR1 expression and endothelial cell function.

Keywords: Angiogenesis; COPD; Epigenetics; LncRNA; S1P.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / metabolism
  • Down-Regulation / genetics
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Lung / metabolism
  • Lysophospholipids / metabolism*
  • Neovascularization, Physiologic
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Lysosphingolipid / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Transcription, Genetic

Substances

  • Lysophospholipids
  • RNA, Long Noncoding
  • RNA, Messenger
  • Receptors, Lysosphingolipid
  • Repressor Proteins
  • ZNF354C protein, human
  • sphingosine 1-phosphate
  • DNA
  • Sphingosine