A Positive Regulatory Loop between a Wnt-Regulated Non-coding RNA and ASCL2 Controls Intestinal Stem Cell Fate.
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.
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece.
Antonis
A
Giakountis
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece.
Panagiotis
P
Moulos
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece; School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Vasiliki
V
Zarkou
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece.
Christina
C
Oikonomou
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece.
Vaggelis
V
Harokopos
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece; DIANA-Lab, Department of Electrical and Computer Engineering, University of Thessaly, 38221 Volos, Greece.
Artemis G
AG
Hatzigeorgiou
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece.
Martin
M
Reczko
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece. Electronic address: hatzis@fleming.gr.
Pantelis
P
Hatzis
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007422:Intestines / Q000473:pathology*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D062085:RNA, Long Noncoding; C065501:ASCL2 protein, human; C000623201:long non-coding RNA WiNTRLINC1, human