Long non-coding RNA and microRNAs might act in regulating the expression of BARD1 mRNAs

Int J Biochem Cell Biol. 2014 Sep;54:356-67. doi: 10.1016/j.biocel.2014.06.018. Epub 2014 Jul 5.

Abstract

Long non-coding RNAs (lncRNAs) are ubiquitously expressed RNA molecules of more than 200 nucleotides without substantial ORFs. LncRNAs could act as epigenetic regulators of gene expression affecting transcription, mRNA stability and transport, and translation, although, precise functions have been attributed to only few of them. Competing endogenous RNAs (ceRNAs) represent one recently emerged type of functional lncRNAs that share microRNA recognition sequences with mRNAs and may compete for microRNA binding and thus affect regulation and function of target mRNAs. We studied the epigenetic regulation of the BARD1 gene. The BARD1 protein acts as tumor suppressor with BRCA1. In cancer, mRNAs encoding the tumor suppressor full length BARD1 are often down-regulated while the expression of oncogenic truncated isoforms is boosted. We found that the BARD1 3'UTR is almost 3000nt long and harbors a large number of microRNA binding elements. In addition we discovered a novel lncRNA, BARD1 9'L, which is transcribed from an alternative promoter in intron 9 of the BARD1 gene and shares part of the 3'UTR with the protein coding BARD1 mRNAs. We demonstrate with the example of two microRNAs, miR-203 and miR-101, that they down-regulate the expression of FL BARD1 and cancer-associated BARD1 mRNAs, and that BARD1 9'L counteracts the effect of miR-203 and miR-101, As BARD1 9'L is abnormally over-expressed in human cancers, we suggest it might be a tumor promoting factor and treatment target. This article is part of a Directed Issue entitled: The Non-coding RNA Revolution.

Keywords: Alternative splicing; Neuroblastoma SNP; ceRNA; lncRNA; microRNA.

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Base Sequence
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MicroRNAs / genetics*
  • Molecular Sequence Data
  • Protein Isoforms
  • RNA, Long Noncoding / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA, Neoplasm / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Nucleic Acid
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics*

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • Protein Isoforms
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA, Neoplasm
  • Tumor Suppressor Proteins
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases