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

被引：50

作者：

Giakountis, Antonis ^{[1
]}

Moulos, Panagiotis ^{[1
]}

Zarkou, Vasiliki ^{[1
,2
]}

Oikonomou, Christina ^{[1
,4
,5
]}

Harokopos, Vaggelis ^{[1
]}

Hatzigeorgiou, Artemis G. ^{[1
,3
]}

Reczko, Martin ^{[1
]}

Hatzis, Pantelis ^{[1
]}

机构：

[1] Biomed Sci Res Ctr Alexander Fleming, Vari 16672, Greece

[2] Aristotle Univ Thessaloniki, Sch Biol, Thessaloniki 54124, Greece

[3] Univ Thessaly, Dept Elect & Comp Engn, DIANA Lab, Volos 38221, Greece

[4] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Dept Tumor Cell Biol, Memphis, TN 38105 USA

[5] Univ Tennessee, Hlth Sci Ctr, Integrated Program Biomed Sci, Memphis, TN 38105 USA

来源：

CELL REPORTS | 2016年 / 15卷 / 12期

关键词：

COLORECTAL-CANCER CELLS; GENE-EXPRESSION; CHROMATIN INTERACTIONS; BETA-CATENIN; TRANSCRIPTION; OCCUPANCY; TARGET; SIGNATURE; ASSOCIATE; LEUKEMIA;

D O I：

10.1016/j.celrep.2016.05.038

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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/beta-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/beta-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/beta-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.

引用

页码：2588 / 2596

页数：9

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