Identification of Rtl1, a Retrotransposon-Derived Imprinted Gene, as a Novel Driver of Hepatocarcinogenesis

Jesse D. Riordan, Vincent W. Keng, Barbara R. Tschida, Todd E. Scheetz, Jason B. Bell, Kelly M. Podetz-Pedersen, Catherine D. Moser, Neal G. Copeland, Nancy A. Jenkins, Lewis Rowland Roberts, David A. Largaespada, Adam J. Dupuy

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

We previously utilized a Sleeping Beauty (SB) transposon mutagenesis screen to discover novel drivers of HCC. This approach identified recurrent mutations within the Dlk1-Dio3 imprinted domain, indicating that alteration of one or more elements within the domain provides a selective advantage to cells during the process of hepatocarcinogenesis. For the current study, we performed transcriptome and small RNA sequencing to profile gene expression in SB-induced HCCs in an attempt to clarify the genetic element(s) contributing to tumorigenesis. We identified strong induction of Retrotransposon-like 1 (Rtl1) expression as the only consistent alteration detected in all SB-induced tumors with Dlk1-Dio3 integrations, suggesting that Rtl1 activation serves as a driver of HCC. While previous studies have identified correlations between disrupted expression of multiple Dlk1-Dio3 domain members and HCC, we show here that direct modulation of a single domain member, Rtl1, can promote hepatocarcinogenesis in vivo. Overexpression of Rtl1 in the livers of adult mice using a hydrodynamic gene delivery technique resulted in highly penetrant (86%) tumor formation. Additionally, we detected overexpression of RTL1 in 30% of analyzed human HCC samples, indicating the potential relevance of this locus as a therapeutic target for patients. The Rtl1 locus is evolutionarily derived from the domestication of a retrotransposon. In addition to identifying Rtl1 as a novel driver of HCC, our study represents one of the first direct in vivo demonstrations of a role for such a co-opted genetic element in promoting carcinogenesis.

Original languageEnglish (US)
Article numbere1003441
JournalPLoS Genetics
Volume9
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Retroelements
retrotransposons
tumor
gene
domestication
Beauty
Genes
gene expression
RNA
mutation
genes
hydrodynamics
Transcriptome
carcinogenesis
Carcinogenesis
RNA Sequence Analysis
loci
neoplasms
Hydrodynamics
gene transfer

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Riordan, J. D., Keng, V. W., Tschida, B. R., Scheetz, T. E., Bell, J. B., Podetz-Pedersen, K. M., ... Dupuy, A. J. (2013). Identification of Rtl1, a Retrotransposon-Derived Imprinted Gene, as a Novel Driver of Hepatocarcinogenesis. PLoS Genetics, 9(4), [e1003441]. https://doi.org/10.1371/journal.pgen.1003441

Identification of Rtl1, a Retrotransposon-Derived Imprinted Gene, as a Novel Driver of Hepatocarcinogenesis. / Riordan, Jesse D.; Keng, Vincent W.; Tschida, Barbara R.; Scheetz, Todd E.; Bell, Jason B.; Podetz-Pedersen, Kelly M.; Moser, Catherine D.; Copeland, Neal G.; Jenkins, Nancy A.; Roberts, Lewis Rowland; Largaespada, David A.; Dupuy, Adam J.

In: PLoS Genetics, Vol. 9, No. 4, e1003441, 04.2013.

Research output: Contribution to journalArticle

Riordan, JD, Keng, VW, Tschida, BR, Scheetz, TE, Bell, JB, Podetz-Pedersen, KM, Moser, CD, Copeland, NG, Jenkins, NA, Roberts, LR, Largaespada, DA & Dupuy, AJ 2013, 'Identification of Rtl1, a Retrotransposon-Derived Imprinted Gene, as a Novel Driver of Hepatocarcinogenesis', PLoS Genetics, vol. 9, no. 4, e1003441. https://doi.org/10.1371/journal.pgen.1003441
Riordan, Jesse D. ; Keng, Vincent W. ; Tschida, Barbara R. ; Scheetz, Todd E. ; Bell, Jason B. ; Podetz-Pedersen, Kelly M. ; Moser, Catherine D. ; Copeland, Neal G. ; Jenkins, Nancy A. ; Roberts, Lewis Rowland ; Largaespada, David A. ; Dupuy, Adam J. / Identification of Rtl1, a Retrotransposon-Derived Imprinted Gene, as a Novel Driver of Hepatocarcinogenesis. In: PLoS Genetics. 2013 ; Vol. 9, No. 4.
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