Screening for small-molecule modulators of long noncoding RNA-protein interactions using alphascreen

Roya Pedram Fatemi, Sultan Salah-Uddin, Farzaneh Modarresi, Nathalie Khoury, Claes Wahlestedt, Mohammad Ali Faghihi

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Long non-protein coding RNAs (lncRNAs) are an important class of molecules that help orchestrate key cellular events. Although their functional roles in cells are not well understood, thousands of lncRNAs and a number of possible mechanisms by which they act have been reported. LncRNAs can exert their regulatory function in cells by interacting with epigenetic enzymes. In this study, we developed a tool to study lncRNA-protein interactions for high-throughput screening of small-molecule modulators using AlphaScreen technology. We tested the interaction of two lncRNAs: brain-derived neurotrophic factor antisense (BDNF-AS) and Hox transcript antisense RNA (HOTAIR), with Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase against a phytochemical library, to look for small-molecule inhibitors that can alter the expression of downstream target genes. We identified ellipticine, a compound that up-regulates BDNF transcription. Our study shows the feasibility of using high-throughput screening to identify modulators of lncRNA-protein interactions and paves the road for targeting lncRNAs that are dysregulated in human disorders using small-molecule therapies.

Original languageEnglish (US)
Pages (from-to)1132-1141
Number of pages10
JournalJournal of Biomolecular Screening
Volume20
Issue number9
DOIs
StatePublished - Oct 22 2015

Keywords

  • AlphaScreen
  • Enhancer of zeste homolog 2 (EZH2)
  • RNA protein interaction
  • brain-derived neurotrophic factor (BDNF)
  • brain-derived neurotrophic factor antisense (BDNFAS)
  • epigenetic enzyme
  • hox transcript antisense RNA (HOTAIR)
  • long noncoding RNA
  • natural antisense transcript
  • noncoding RNA

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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