Poster Presentation Epigenetics 2013

CRNDE – A long non-coding RNA involved in development, energy metabolism and cancer (#209)

Lloyd D. Graham 1 2 , Blake C. Ellis 1 2 , Peter L. Molloy 1 2
  1. CSIRO Preventative Health Flagship, North Ryde, NSW, Australia
  2. CSIRO Animal, Food & Health Sciences, North Ryde, NSW, Australia

CRNDE  (Colorectal Neoplasia Differentially Expressed) encodes multiple splice variants of a cancer-associated long non-coding RNA (lncRNA).1  CRNDE transcripts that retain intronic segments are confined to the nucleus, while fully-spliced transcripts are found in the cytoplasm.2  Knockdown of CRNDE transcripts, especially the nuclear ones, decreases growth and increases apoptosis in CRC cells, while knock-in of CRNDE segments promotes proliferation, including anchorage-independent growth.2  The nuclear splice isoforms of CRNDE are believed to provide specific functional scaffolds for chromatin-modifying complexes such as PRC2 and CoREST, which they then pilot to genes targeted for epigenetic silencing.3  

CRNDE was initially identified as a lncRNA whose expression is highly elevated in colorectal cancer,1  but it is also upregulated in many other solid tumors and in leukemias.2  Indeed, CRNDE is the most upregulated lncRNA in gliomas4  and here, as in other cancers, it is associated with a “stemness” signature. Expression of mouse CRNDE is high in iPSC,5  and its knockdown in moESC causes a decrease in the levels of transcription factors essential for pluripotency.6  Surprisingly, mouse CRNDE increases even further during the differentiation of iPSCs into neurons.5  CRNDE may silence mesodermal lineage genes in general and, in the developing neuroectoderm, suppress glial fate in particular. In normal adult tissues, CRNDE expression generally correlates with that of the adjacent gene IRX5, which is on the opposite strand.2  Recently we have discovered that CRNDE nuclear transcripts are regulated by insulin and IGFs, and it seems that they may mediate some of insulin’s effects on its target genes.7  Moreover, the effect on the transcriptome of knocking down CRNDE nuclear transcripts suggests that these lncRNAs may inhibit oxidative phosphorylation (the energy metabolism typical of normal cells) and promote aerobic glycolysis (the Warburg effect, typical of cancer cells).

  1. Graham et al., Colorectal Neoplasia Differentially Expressed (CRNDE), a Novel Gene with Elevated Expression in Colorectal Adenomas and Adenocarcinomas. Genes Cancer. 2011;2(8):829-40.
  2. Ellis et al., CRNDE: A Long Non-Coding RNA Involved in CanceR, Neurobiology, and DEvelopment. Front Genet. 2012;3:270.
  3. Khalil et al., Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009;106(28):11667-72.
  4. Leung et al., Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiol Dis. 2012;48(1):1-8.
  5. Lin et al., RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS One. 2011;6(9):e23356.
  6. Guttman et al., lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011;477(7364):295-300.
  7. Ellis et al., CRNDE, a novel non-coding RNA (ncRNA) gene with elevated expression in colorectal neoplasia. Human Genome Meeting, March 2012, Genetics and Genomics in Personalised Medicine, Sydney, P026.