title: Identification of rtl1, a retrotransposon-derived imprinted gene, as a novel driver of hepatocarcinogenesis.
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.
authors.affiliation: Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Riordan
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Keng
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Tschida
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.forename: Jason B
authors.initials: JB
authors.lastname: Bell
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Podetz-Pedersen
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002883:Chromosomes, Human, Pair 14 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics*; D019895:Transposases / Q000378:metabolism
chemical_list: D011257:Pregnancy Proteins; C579465:RTL1 protein, human; D018626:Retroelements; C526773:Rtl1 protein, mouse; D019895:Transposases; C494471:sleeping beauty transposase, human