Regulation of miR-200c/141 expression by intergenic DNA-looping and transcriptional read-through

Nat Commun. 2016 Jan 4:7:8959. doi: 10.1038/ncomms9959.

Abstract

The miR-200 family members have been implicated in stress responses and ovarian tumorigenesis. Here, we find that miR-200c/141 transcription is intimately linked to the transcription of the proximal upstream gene PTPN6 (SHP1) in all physiological conditions tested. PTPN6 and miR-200c/141 are transcriptionally co-regulated by two complementary mechanisms. First, a bypass of the regular PTPN6 polyadenylation signal allows the transcription of the downstream miR-200c/141. Second, the promoters of the PTPN6 and miR-200c/141 transcription units physically interact through a 3-dimensional DNA loop and exhibit similar epigenetic regulation. Our findings highlight that transcription of intergenic miRNAs is a novel outcome of transcriptional read-through and reveal a yet unexplored type of DNA loop associating two closely located promoters. These mechanisms have significant relevance in ovarian cancers and stress response, pathophysiological conditions in which miR-200c/141 exert key functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA, Intergenic / metabolism*
  • Epigenomics
  • Female
  • Gene Expression Regulation / physiology*
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Signal Transduction
  • Transcription, Genetic

Substances

  • DNA, Intergenic
  • MIRN141 microRNA, human
  • MIRN200 microRNA, human
  • MicroRNAs
  • Mirn141 microRNA, mouse
  • Mirn200 microRNA, mouse
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse