A Positive Regulatory Loop between a Wnt-Regulated Non-coding RNA and ASCL2 Controls Intestinal Stem Cell Fate

Cell Rep. 2016 Jun 21;15(12):2588-96. doi: 10.1016/j.celrep.2016.05.038. Epub 2016 Jun 9.


The canonical Wnt pathway plays a central role in stem cell maintenance, differentiation, and proliferation in the intestinal epithelium. Constitutive, aberrant activity of the TCF4/β-catenin transcriptional complex is the primary transforming factor in colorectal cancer. We identify a nuclear long non-coding RNA, termed WiNTRLINC1, as a direct target of TCF4/β-catenin in colorectal cancer cells. WiNTRLINC1 positively regulates the expression of its genomic neighbor ASCL2, a transcription factor that controls intestinal stem cell fate. WiNTRLINC1 interacts with TCF4/β-catenin to mediate the juxtaposition of its promoter with the regulatory regions of ASCL2. ASCL2, in turn, regulates WiNTRLINC1 transcriptionally, closing a feedforward regulatory loop that controls stem cell-related gene expression. This regulatory circuitry is highly amplified in colorectal cancer and correlates with increased metastatic potential and decreased patient survival. Our results uncover the interplay between non-coding RNA-mediated regulation and Wnt signaling and point to the diagnostic and therapeutic potential of WiNTRLINC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Line, Tumor
  • Cell Lineage / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intestines / pathology*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Stem Cells / metabolism*
  • Wnt Signaling Pathway* / genetics


  • ASCL2 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • RNA, Long Noncoding
  • long non-coding RNA WiNTRLINC1, human