Editorial: mobile genetic elements in cellular differentiation, genome stability, and cancer

Editorial on the Research Topic
Mobile Genetic Elements in Cellular Differentiation, Genome Stability, and Cancer

The human genome, as well as the genome of most organisms, harbors various types and abundances of transposable element derived repeats ( Lander, 2001 ; Waterston et al., 2002 ). The topic on: “ Mobile Genetic Elements in Cellular Differentiation, Genome Stability, and Cancer,” includes a collection of original research articles and reviews, which address the impact of reverse transcriptases, including the ones coded by transposable elements, on both basic biological mechanisms and disease. In 1970, the discovery of reverse transcriptases or RNA-dependent DNA polymerases, was reported by two different laboratories ( Baltimore, 1970 ; Temin and Mizutani, 1970 ). Since then numerous studies regarding retroviral reverse transcriptases have significantly contributed to the characterization and biology of may different retrovirus and retroelements. These studies continue to be of interest for the prevention and treatment of various retroviral induced human diseases and for the basic understanding of the origin of retroviruses. In addition the knowledge of reverse transcription has been harnessed for basic use in molecular biology and other applications, including recent widely used methods such as RNAseq. As retroviruses are considered exogenously derived reverse transcriptases, the subsequent discovery in 1987 of telomerase, also considered an endogenous RNA-dependent DNA polymerase, has significantly contributed to the understanding of one of the predominant mechanisms of telomere maintenance that contributes to most, but not all organisms with linear chromosomes ( Greider and Blackburn, 1985 ; Biessmann et al., 1990 ). Yet, sequences encoding for endogenous RNA-dependent DNA polymerases are not limited to telomerase. The isolation and subsequent genetic, biochemical, and molecular characterization of human full-length non-Long Terminal Repeat (LTR) retrotransposons, termedLongInterspersedElements (LINE-1) demonstrated that elements formally encode a reverse transcriptase activity ( Dombroski et al., 1991 ; Mathias et al., 1991 ; Feng et al., 1996 ; Moran et al., 1996 ). Non-LTR retrotransposons are not limited to the human genome, and are present as full-length and/or truncated, rearranged, inactive remnants in many other genomes. In addition, the reverse transcriptase activities encoded by non-LTR retrotransposons share sequence identity with many other reverse transcriptases ( Nakamura et al., 1997 ; Malik et al., 1999 ). Furthermore, non-LTR retrotransposons rely on the encoded reverse transcriptase for integration, typically by target-primed reverse transcription (TPRT), which was initially biochemically defined using the non-LTR retrotransposon R2Bm, from Bombyx mori ( Luan et al., 1993 ). A review by Onozawa and Aplan included in this topic, describes two different types of LINE-1 reverse transcriptase-mediated template sequence insertion polymorphisms (TSIPs), or integration structures that are polymorphic in the human genome ( Onozawa and Aplan ). The characteristics of class2 structures allude to the occurrence of additional integration mechanisms by the LINE-1 reverse transcriptase that may occur in germ cells or during embryogenesis ( Onozawa and Aplan ). To note, the features described in these class2 structures are consistent with previous reports of endonuclease-independent LINE-1 retrotransposition ( Eickbush, 2002 ; Morrish et al., 2002 ).

Phylogenetic analysis of the reverse transcriptase domains support the idea that retroviruses and telomerase evolved from non-LTR retrotransposons, due to the gain or loss of LTR sequence and/or sequences encoding for specific domains ( Xiong and Eickbush, 1988 ; Malik et al., 1999 ). These early phylogenetic studies are consistent with the protovirus hypothesis proposed by Temin, that (1) retroviruses are likely derived from endogenous retrotransposons and (2) mutations that arise due to the mobility of retrotransposons could potentially activate oncogenes or inactivate tumor suppressor genes, perhaps contributing to tumorigenesis ( Temin, 1971 ; Shimotohno et al., 1980 ). As LINE-1 elements are active in tumors, yet transcriptionally repressed in many somatic cell types, there was much interest to understand the extent that LINE-1 retrotransposition contributes to tumorigenesis ( Solyom et al., 2012 ; Shukla et al., 2013 ; Doucet-O’Hare et al., 2015 ; Ewing et al., 2015 ; Rodic et al., 2015 ). Included in this topic is original research using bioinformatic approaches to examine LINE-1 expression and insertion profiles using RNA-seq data from normal and primary tumor samples collected using the Cancer Genome Atlas (TCGA) ( Clayton et al.). Here the authors examined the expression and integration differences in breast invasive carcinoma, head and neck squamous carcinoma, and lung adenocarcinoma and their analysis indicates two cases of LINE-1 mediated insertions near two different tumor suppressor genes, including an Alu insertion into the CBL gene in breast invasive carcinoma and a LINE-1 insertion into the first exon of the BAALC gene in a head and neck squamous cell carcinoma. Again, these findings are consistent with the protovirus hypothesis. However these tumors may also harbor mutations in “ host” genes that regulate LINE-1 retrotransposition. A number of reviews were included in this topic that address recent studies on LINE-1 retrotransposition in cancer ( Honda ; Kemp and Longworth ; Sciamanna et al.). In addition, identifying cellular genes and pathways that regulate LINE-1 transcription and activity is an active area of research, and two reviews discuss the current understanding regarding the regulation of LINE-1 retrotransposition in somatic cells, which may become dysregulated in cancer ( Ariumi ; Pizarro and Cristofari ). The topic also includes two original research articles on the impact of endogenous retroviruses on genome evolution. In the article by Irie et al., the authors use dN/dS analysis and molecular approaches to validate their findings regarding the contribution of the sushi-ichi retrotransposon during the evolution of the zinc finger protein-encoding gene SIRH11/ZCCHC16 and the impact of this gene during eutherian brain evolution. In addition, another research article examines the evolution of the Tbx6 transcription binding sites, (ORRA1-ORRA1D), which are LTRs derived from the endogenous retroviruses, MaLRs ( Yasuhiko et al.). The authors examine the impact on transcription of genes harboring these Tbx6 binding sites, using the Tbx6 knockout mouse. Their findings are coupled with biochemical and bioinformatic approaches. Finally two reviews nicely described the host cellular factors that impact the transcriptional dynamics of ERVs in the human genome ( Buzdin et al.; Meyer et al.).

Overall the articles that were received for this topic: “ Mobile Genetic Elements in Cellular Differentiation, Genome Stability, and Cancer” predominantly focus on the evolution of endogenous reverse transcriptases (RT), including the LINE-1 encoded RT, and the endogenous retroviruses ERVs and MaLR. These articles also summarize the findings in the field regarding these reverse transcriptases in normal biology and disease. These summaries and newly reported findings are consistent with the protovirus hypothesis ( Temin, 1971 ; Shimotohno et al., 1980 ; Shimotohno and Temin, 1981 ). Identification of additional host factors and cellular pathways that contribute to LINE-1 retrotransposition will help further elucidate the protovirus hypothesis, as not all LINE-1 insertions occur in tumor suppressor or oncogenes. In addition, further studies regarding exogenous and endogenous reverse transcriptases will continue to shed light on the growing knowledge surrounding reverse transcription in the RNA world.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Funding

Funding was provided by a Howard Temin Pathway to Independence Award, Grant Number K99/R00CA154889 from the National Cancer Institute (TM) and the deArce Koch Memorial Endowment Fund from the University of Toledo (TM). JG-P’s lab is supported by CICE-FEDER-P12-CTS-2256, Plan Nacional de I+D+I 2008–2011 and 2013–2016 (FIS-FEDER-PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), by The Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISFF2) and by a private donation by Ms. Francisca Serrano (Trading y Bolsa para Torpes, Granada, Spain).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Baltimore, D. (1970). RNA-dependent DNA polymerase in virions of RNA tumour viruses. Nature 226, 1209–1211. doi: 10. 1038/2261209a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Biessmann, H., Mason, J. M., Ferry, K., d’Hulst, M., Valgeirsdottir, K., Traverse, K. L., et al. (1990). Addition of telomere-associated HeT DNA sequences “ heals” broken chromosome ends in Drosophila . Cell 61, 663–673. doi: 10. 1016/0092-8674(90)90478-W

PubMed Abstract | CrossRef Full Text | Google Scholar

Dombroski, B. A., Mathias, S. L., Nanthakumar, E., Scott, A. F., and Kazazian, H. H. Jr. (1991). Isolation of an active human transposable element. Science 254, 1805–1808. doi: 10. 1126/science. 1662412

PubMed Abstract | CrossRef Full Text | Google Scholar

Doucet-O’Hare, T. T., Rodic, N., Sharma, R., Darbari, I., Abril, G., Choi, J. A., et al. (2015). LINE-1 expression and retrotransposition in Barrett’s esophagus and esophageal carcinoma. Proc. Natl. Acad. Sci. U. S. A. 112, E4894–E4900. doi: 10. 1073/pnas. 1502474112

PubMed Abstract | CrossRef Full Text | Google Scholar

Eickbush, T. H. (2002). Repair by retrotransposition. Nat. Genet. 31, 126–127. doi: 10. 1038/ng897

PubMed Abstract | CrossRef Full Text | Google Scholar

Ewing, A. D., Gacita, A., Wood, L. D., Ma, F., Xing, D., Kim, M. S., et al. (2015). Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Res. 25, 1536–1545. doi: 10. 1101/gr. 196238. 115

PubMed Abstract | CrossRef Full Text | Google Scholar

Feng, Q., Moran, J. V., Kazazian, H. H. Jr., and Boeke, J. D. (1996). Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87, 905–916. doi: 10. 1016/S0092-8674(00)81997-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Greider, C. W., and Blackburn, E. H. (1985). Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413. doi: 10. 1016/0092-8674(85)90170-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Lander, E. S. (2001). Initial impact of the sequencing of the human genome. Nature 470, 187–197. doi: 10. 1038/nature09792

PubMed Abstract | CrossRef Full Text | Google Scholar

Luan, D. D., Korman, M. H., Jakubczak, J. L., and Eickbush, T. H. (1993). Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell 72, 595–605. doi: 10. 1016/0092-8674(93)90078-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Malik, H. S., Burke, W. D., and Eickbush, T. H. (1999). The age and evolution of non-LTR retrotransposable elements. Mol. Biol. Evol. 16, 793–805. doi: 10. 1093/oxfordjournals. molbev. a026164

PubMed Abstract | CrossRef Full Text | Google Scholar

Mathias, S. L., Scott, A. F., Kazazian, H. H. Jr., Boeke, J. D., and Gabriel, A. (1991). Reverse transcriptase encoded by a human transposable element. Science 254, 1808–1810. doi: 10. 1126/science. 1722352

PubMed Abstract | CrossRef Full Text | Google Scholar

Moran, J. V., Holmes, S. E., Naas, T. P., DeBerardinis, R. J., Boeke, J. D., and Kazazian, H. H. Jr. (1996). High frequency retrotransposition in cultured mammalian cells. Cell 87, 917–927. doi: 10. 1016/S0092-8674(00)81998-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Morrish, T. A., Gilbert, N., Myers, J. S., Vincent, B. J., Stamato, T. D., Taccioli, G. E., et al. (2002). DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nat. Genet. 31, 159–165. doi: 10. 1038/ng898

PubMed Abstract | CrossRef Full Text | Google Scholar

Nakamura, T. M., Morin, G. B., Chapman, K. B., Weinrich, S. L., Andrews, W. H., Lingner, J., et al. (1997). Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959. doi: 10. 1126/science. 277. 5328. 955

PubMed Abstract | CrossRef Full Text | Google Scholar

Rodic, N., Steranka, J. P., Makohon-Moore, A., Moyer, A., Shen, P., Sharma, R., et al. (2015). Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nat. Med. 21, 1060–1064. doi: 10. 1038/nm. 3919

PubMed Abstract | CrossRef Full Text | Google Scholar

Shimotohno, K., Mizutani, S., and Temin, H. M. (1980). Sequence of retrovirus provirus resembles that of bacterial transposable elements. Nature 285, 550–554. doi: 10. 1038/285550a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Shimotohno, K., and Temin, H. M. (1981). Evolution of retroviruses from cellular movable genetic elements. Cold Spring Harb Symp. Quant. Biol. 45 (Pt)2, 719–730. doi: 10. 1101/SQB. 1981. 045. 01. 090

PubMed Abstract | CrossRef Full Text | Google Scholar

Shukla, R., Upton, K. R., Munoz-Lopez, M., Gerhardt, D. J., Fisher, M. E., Nguyen, T., et al. (2013). Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 153, 101–111. doi: 10. 1016/j. cell. 2013. 02. 032

PubMed Abstract | CrossRef Full Text | Google Scholar

Solyom, S., Ewing, A. D., Rahrmann, E. P., Doucet, T., Nelson, H. H., Burns, M. B., et al. (2012). Extensive somatic L1 retrotransposition in colorectal tumors. Genome Res. 22, 2328–2338. doi: 10. 1101/gr. 145235. 112

PubMed Abstract | CrossRef Full Text | Google Scholar

Temin, H. M. (1971). The protovirus hypothesis: speculations on the significance of RNA-directed DNA synthesis for normal development and for carcinogenesis. J. Natl. Cancer Inst. 46, 3–7.

PubMed Abstract

Temin, H. M., and Mizutani, S. (1970). RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 226, 1211–1213. doi: 10. 1038/2261211a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Waterston, R. H., Lindblad-Toh, K., Birney, E., Rogers, J., Abril, J. F., Agarwal, P., et al. (2002). Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562. doi: 10. 1038/nature01262

PubMed Abstract | CrossRef Full Text | Google Scholar

Xiong, Y. E., and Eickbush, T. H. (1988). Functional expression of a sequence-specific endonuclease encoded by the retrotransposon R2Bm. Cell 55, 235–246. doi: 10. 1016/0092-8674(88)90046-3

PubMed Abstract | CrossRef Full Text | Google Scholar