lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators

Cell Rep. 2019 Mar 12;26(11):2904-2915.e4. doi: 10.1016/j.celrep.2019.02.059.

Abstract

Transcription of the proto-oncogene SPHK1 is regulated by KHPS1, an antisense RNA that activates SPHK1 expression by forming a triple-helical RNA-DNA-DNA structure at the SPHK1 enhancer. Triplex-mediated tethering of KHPS1 to its target gene is required for recruitment of E2F1 and p300 and transcription of the RNA derived from the SPHK1 enhancer (eRNA-Sphk1). eRNA-Sphk1 evicts CTCF, which insulates the enhancer from the SPHK1 promoter, thus facilitating SPHK1 expression. Genomic deletion of the triplex-forming sequence attenuates SPHK1 expression, leading to decreased cell migration and invasion. Replacement of the triplex-forming region (TFR) of KHPS1 by the TFR of the lncRNA MEG3 tethers KHPS1 to the MEG3 target gene TGFBR1, underscoring the interchangeability and anchoring function of sequences involved in triplex formation. Altogether, the results reveal a triplex-driven feedforward mechanism involving lncRNA-dependent induction of eRNA, which enhances expression of specific target genes.

Keywords: CTCF; E2F1; RNA-DNA triplexes; SPHK1; eRNA; lncRNA; p300; poised enhancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Enhancer Elements, Genetic*
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Humans
  • Mice
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Receptor, Transforming Growth Factor-beta Type I / metabolism

Substances

  • Khps1 long noncoding RNA, human
  • MEG3 non-coding RNA, human
  • RNA, Long Noncoding
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human