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Genetic and Epigenetic Regulation of LINE-1 Retrotransposons

L1 replicates exclusively inside individual cells, involving steps such as transcription, translation, target-primed reverse transcription and integration. Using mammalian cell culture and transgenic mouse as primary systems, we are interested in dissecting mechanisms of L1 retrotransposition, especially host factors involved in genetic and epigenetic regulation of L1 activity and evolutionary dynamics.

Functional Impacts of LINE-1 retrotransposons

L1 is the only active autonomous transposable element in the human genome and it has been replicating in mammals since before the mammalian radiation. We are interested in developing novel mouse models and using them to investigate the impacts of L1 retrotransposition on genomic structure and function. We are particularly interested in the timing of L1 retrotransposition and the corresponding mutational burden during animal development and cancer progression.

1. Moran J.V., Holmes S.E., Naas T.P., DeBerardinis R.J., Boeke J.D. and Kazazian H.H., Jr. High frequency retrotransposition in cultured mammalian cells. Cell 87, 917-927 (1996). PMID: 8945518. First demonstration of L1 retrotransposition in cell culture
2. Szak S.T., Pickeral O.K., Makalowski W., Boguski M.S., Landsman D. and Boeke J.D. Molecular archeology of L1 insertions in the human genome. Genome Biology 3, research0052 (2002). PMID: 12372140. Detailed account of L1 characteristics in our genome
3. Han J.S. and Boeke J.D. A highly active synthetic mammalian retrotransposon. Nature 429, 314-318. (2004) PMID: 15152256. The genesis of a synthetic L1, later known as ORFeus
4. Hancks D.C., Kazazian H.H. Jr. Active human retrotransposons: variation and disease. Current Opinion in Genetics and Development. 22(3):191-203 (2012).PMID: 22406018. A comprehensive catalog of sporadic diseases caused by human retrotransposons
5. Rosser, J.M. and An, W. L1 expression and regulation in humans and rodents. Frontiers in Bioscience E4:2203-25 (2012). PMID: 22202032. Our own review on L1 expression and regulation. 
6. Bao J., Yan W. Male germline control of transposable elements. Biology of Reproduction 86(5):162, 1-14 (2012). PMID: 22357546. A recent review of retrotransposon regulation in the male germ line
7. Sedivy J.M., Kreiling J.A., Neretti N., De Cecco M., Criscione S.W., Hofmann J.W., Zhao X., Ito T., Peterson A.L. Death by transposition - the enemy within? Bio essays. 35(12):1035-43 (2013). PMID: 24129940. A recent review of the role of retrotransposition in cellular senescence and aging
8. Carreira P.E., Richardson S.R., Faulkner G.J. L1 retrotransposons, cancer stem cells and oncogenesis. FEBS J. 281(1):63-73 (2014). PMID: 24286172. A recent review of the role of retrotransposition in oncogenesis
9. Volkman H.E., Stetson D.B. The enemy within: endogenous retroelements and autoimmune disease. Nature Immunology 15(5):415-22 (2014). PMID: 24747712. A recent review of the role of retrotransposition in autoimmune diseases
10. Erwin JA, Marchetto MC, Gage FH. Mobile DNA elements in the generation of diversity and complexity in the brain. Nature Reviews Neurosciences 15(8):497-506 (2014). PMID: 25005482. A recent review of the role of retrotransposition during neurogenesis and in neurological disorders

And, of course, many more can be found by a PubMed Search.

Kong L, Saha S, Hu Y, Tschetter JN, Habben CE, Whitmore LS, Yao C, Ge X, Ye P, Newkirk SJ, An W. Subfamily-specific differential contribution of individual monomers and the tether sequence to mouse L1 promoter activity. Mobile DNA, 13 (2022). PMID: 35443687. PMCID: PMC9022269. DOI: 10.1186/s13100-022-00269-z. Posted December 04, 2021 on bioRxiv (initial version)

Gu Z, Liu Y, Zhang Y, Cao H, Lyu J, Wang X, Wylie A, Newkirk SJ, Jones AE, Lee M Jr., Botten GA, Deng M, Dickerson KE, Zhang CC, An W, Abrams JM, & Xu J. Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. Nature Genetics, 53:672–682 (2021). PMID: 33833453. PMCID: PMC8270111. DOI: 10.1038/s41588-021-00829-8

Newkirk SJ, Kong L, Jones MM, Habben CE, Dilts VL, Ye P, & An W. Subfamily-specific quantification of endogenous L1 retrotransposons by droplet digital PCR. Analytical Biochemistry, 601:113779 (2020). PMID: 32442414. PMCID: PMC7714369. DOI: 10.1016/j.ab.2020.113779

Liu R, Sreenivasan C, Yu H, Sheng Z, Newkirk SJ, An W, Smith DF, Chen X, Wang D, & Li F. Influenza D virus diverges from its related influenza C virus in the recognition of 9-O-acetylated N-acetyl- or N-glycolyl-neuraminic acid-containing glycan receptors. Virology, 545:16-23 (2020). PMID: 32174455. PMCID: PMC7174096. DOI: 10.1016/j.virol.2020.02.007

Newkirk SJ, & An W. UHRF1: a jack of all trades, and a master epigenetic regulator during spermatogenesis. Biology of Reproduction, 102:1147-1152 (2020). PMID: 32101289. PMCID: PMC7253785. DOI: 10.1093/biolre/ioaa026

Ray DA, Paulat N, An W, Boissinot S, Cordaux R, Kaul T, Freeman B, & Belancio V. The 2019 FASEB Science Research Conference on The Mobile DNA Conference: 25 Years of Discussion and Research, June 23–28, Palm Springs, California, USA. FASEB Journal, 33(11):11625-11628 (2019). PMID: 31671501. DOI: 10.1096/fj.201902390

Vazquez BN, Thackray JK, Simonet N, Chahar S, Kane-Goldsmith N, Newkirk SJ, Lee S, Xing J, Verzi MP, An W, Vaquero A, Tischfield JA, & Serrano L. SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina. Nucleic Acids Research, 47:7870–7885 (2019). PMID: 31226208. PMCID: PMC6735864. DOI: 10.1093/nar/gkz519

Wang Z, McSwiggin H, Newkirk SJ, Wang Y, Oliver D, Tang C, Lee S, Wang S, Yuan S, Zheng H, Ye P, An W, & Yan W. Insertion of a chimeric retrotransposon sequence in mouse Axin1 locus causes metastable kinky tail phenotype. Mobile DNA, 10:17 (2019). PMID: 31073336. PMCID: PMC6500023. DOI: 10.1186/s13100-019-0162-7

Saha P, & An W. Recently Mobilized Transposons in the Human Genome. In: Encyclopedia of Life Sciences. John Wiley & Sons Ltd, Chichester. (2019). DOI: 10.1002/9780470015902.a0020837 (Download PDF)

Reznik B, Cincotta SA, Jaszczak RG, Mateo LJ, Shen J, Cao M, Baskin L, Ye P, An W, & Laird DJ. Heterogeneity of transposon expression and activation of the repressive network in human fetal germ cells. Development 146(12):dev171157 (2019). PMID: 30658985. PMCID: PMC6602354 . DOI: 10.1242/dev.171157

Kawano K, Doucet AJ, Ueno M, Kariya R, An W, Marzetta F, Kuroki M, Turelli P, Sukegawa S, Okada S, Strebel K, Trono D, & Ariumi Y. HIV-1 Vpr and p21 restrict LINE-1 mobility. Nucleic Acids Research 46:8454–8470 (2018). PMID: 30085096. PMCID: PMC6144823. DOI: 10.1093/nar/gky688

Sheng Z, Liu R, Yu J, Ran Z, Newkirk SJ, An W, Li F, & Wang D. Identification and characterization of viral defective RNA genomes in influenza B virus. Journal of General Virology 99(4):475-488 (2018). PMID: 29458654. PMCID: PMC5982128. DOI: 10.1099/jgv.0.001018

Newkirk SJ, Lee S, Grandi FC, Gaysinskaya V, Rosser JM, Vanden Berg N, Hogarth CA, Marchetto MCN, Muotri AR, Griswold MD, Ye P, Bortvin A, Gage FH, Boeke JD, & An W. Intact piRNA pathway prevents L1 mobilization in male meiosis. Proc Natl Acad Sci U S A 114:E5635–E5644 (2017). PMID: 28630288. PMCID: PMC5514719. DOI: 10.1073/pnas.1701069114. Commented by: Wang PJ. Tracking LINE1 retrotransposition in the germline. Proc Natl Acad Sci U S A 114:7194–7196 (2017). Highlighted by: Chen C. A novel reporter mouse to monitor in vivo retrotransposition in the germline. Biology of Reproduction 97:335-336 (2017)

Kannan M, Li J, Fritz SE, Husarek KE, Sanford JC, Sullivan TL, Tiwary PK, An W, Boeke JD, & Symer EE. Dynamic silencing of somatic L1 retrotransposon insertions reflects the developmental and cellular contexts of their genomic integration. Mobile DNA 8:8 (2017). PMID: 28491150. PMCID: PMC5424313. DOI: 10.1186/s13100-017-0091-2.

Newkirk SJ, & An W. L1 Regulation in Mouse and Human Germ Cells. in Human Retrotransposons in Health and Disease, ed Cristofari G (Springer International Publishing), pp 29-61 (2017). DOI: 10.1007/978-3-319-48344-3_2. (PDF available)

Kharytonchyk S, King SR, Ndongmo CB, Stilger KL, An W, & Telesnitsky A. Resolution of Specific Nucleotide Mismatches by Wild-Type and AZT-Resistant Reverse Transcriptases during HIV-1 Replication. Journal of Molecular Biology. 428:2275–2288 (2016). PMID: 27075671. PMCID: PMC4884515. DOI: 10.1016/j.jmb.2016.04.005.

Grandi FC, Rosser JM, Newkirk SJ, Yin J, Jiang X, Xing Z, Whitmore L, Bashir S, Ivics Z, Izsvák Z, Ye P, Yu YE, & An W. Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites. Genome Research. 25:1135-1146 (2015). PMID: 25995269. PMCID: PMC4509998. DOI: 10.1101/gr.185132.114.

Grandi FC, & An W. Non-LTR retrotransposons and microsatellites: Partners in genomic variation. Mobile Genetic Elements. 3:e25674 (2013). PMID: 24195012. PMCID: PMC3812793. DOI: 10.4161/mge.25674.

O'Donnell KA, An W, Schrum CT, Wheelan SJ, & Boeke JD. Controlled insertional mutagenesis using a LINE-1 (ORFeus) gene-trap mouse model. Proc Natl Acad Sci U S A 110:E2706-13 (2013). PMID: 23818630. PMCID: PMC3718180. DOI: 10.1073/pnas.1302504110.

Xie Y, Mates L, Ivics Z, Izsvák Z, Martin SL, & An W. Cell division promotes efficient retrotransposition in a stable L1 reporter cell line. Mobile DNA. 4:10 (2013). PMID: 23497436. PMCID: PMC3607998. DOI: 10.1186/1759-8753-4-10.

Grandi FC, Rosser JM, & An W. LINE-1 derived poly(A) microsatellites undergo rapid shortening and create somatic and germline mosaicism in mice. Molecular Biology and Evolution. 30:503-12 (2013). PMID: 23125228. PMCID: PMC3563966. DOI: 10.1093/molbev/mss251.

Ray D, Hogarth CA, Evans EB, An W, Griswold MD, & Ye P. Experimental validation of Ankrd17 and Anapc10, two novel meiotic genes predicted by computational models in mice. Biology of Reproduction 86(4):102 (2012). PMID: 22190705. PMCID: PMC4480071. DOI: 10.1095/biolreprod.111.095216.

Rosser JM, & An W. L1 expression and regulation in humans and rodents. Frontiers in Bioscience E4:2203-25 (2012). PMID: 22202032. PMCID: PMC4457320. 

An W, Dai L, Niewiadomska AM, Yetil A, O'Donnell KA, Han JS, & Boeke JD. Characterization of a synthetic human LINE-1 retrotransposon ORFeus-Hs. Mobile DNA. 2:2 (2011). PMID: 21320307. PMCID: PMC3045867. DOI: 10.1186/1759-8753-2-2.

Xie Y, Rosser JM, Thompson TL, Boeke JD, & An W. Characterization of L1 retrotransposition with high-throughput dual-luciferase assays. Nucleic Acids Research 39, e16 (2011). PMID: 21320307. PMCID: PMC3045867. DOI: 10.1093/nar/gkq1076.

Rosser JM, & An W. Repeat-induced gene silencing of L1 transgenes is correlated with differential promoter methylation. Gene 456, 15-23 (2010). PMID: 20167267. PMCID: PMC3001326. DOI: 10.1016/j.gene.2010.02.005.

An W, Davis ES, Thompson TL, O'Donnell KA, Lee C-Y, & Boeke JD. Plug and play modular strategies for synthetic retrotransposons. Methods 49, 227-35 (2009). PMID: 19481606. PMCID: PMC2763960. DOI: 10.1016/j.ymeth.2009.05.013.

Han Y, Lin YB, An W, Xu J, Yang HC, O'Connell K, Dordai D, Boeke JD, Siliciano JD, & Siliciano RF. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe 4, 134-46 (2008). PMID: 18692773. PMCID: PMC2604135. DOI: 10.1016/j.chom.2008.06.008.

An W, Han JS, Schrum CM, Maitra A, Koentgen F, & Boeke JD. Conditional activation of a single-copy L1 transgene in mice by Cre. Genesis 46, 373-83 (2008). PMID: 18615728. PMCID: PMC2614868. DOI: 10.1002/dvg.20407.

Boeke JD, An W, Dai L, Davis ES, Han, JS, O'Donnell KA, Scheifele LZ, & Wheelan, S.J. Retrotransposons-natural and synthetic. in Retrotransposition, Diversity and the Brain (eds. Gage, F.H. & Christen, Y.) 21-32 (Springer, 2008). doi:10.1007/978-3-540-74966-0_3. ISBN: 978-3-540-74965-3 (Print) 978-3-540-74966-0 (Online)

An W, Han JS, Wheelan SJ, Davis ES, Coombes CE, Ye P, Triplett C, & Boeke JD. Active retrotransposition by a synthetic L1 element in mice. Proc Natl Acad Sci U S A 103, 18662-7 (2006). PMID: 17124176. PMCID: PMC1693719. DOI: 10.1073/pnas.0605300103.

An W, & Boeke JD. Transposon technology and vertebrate functional genomics. Genome Biology 6, 361 (2005). PMID: 16356279. PMCID: PMC1414074. DOI: 10.1186/gb-2005-6-12-361.

[2024] Jeniffer Atim joins TeamLINE1. Welcome!

[2024] Kick off the New Year with a bioRxiv preprint from TeamLINE1: "YY1 is a transcriptional activator of mouse LINE-1 Tf subfamily!"

[2023] Dr. An receives a pilot grant from Sanford Research.

[2023] Heather Collazo joins TeamLINE1. Welcome!

[2022] Grace Nielsen receives the Joseph F. Nelson Summer Research Scholarship.

[2022] Jada Tschetter receives the Schultz-Werth Award.

[2022] Jacob Devine is accepted into University of South Dakota MD Program.

[2021] Lisa Wipf is featured by "news@SDState". Good job, Lisa!

[2021] First bioRxiv preprint from TeamLINE1: "Subfamily-specific differential contribution of individual monomers and the tether sequence to mouse L1 promoter activity"!

[2021] Raj Naldini joins TeamLINE1. Welcome!

[2021] Dr. An receives SDSU F. O. Butler Award for Excellence in Research.

[2020] Karabi Saha joins our Ph.D. program. Welcome!

[2020] Lingqi Kong passes his Ph.D. final oral exam. Congrats!

[2020] Partha Saha passes his Ph.D. final oral exam. Congrats!

[2019] Dr. An receives an R03 grant from NICHD.

[2019] Both Mason and Chase are accepted into University of South Dakota M.D. Program.

[2019] Heather Collazo joins us this summer as a fellow of the FAST REEU program.

[2019] Trenton LaCanne receives the Joseph F. Nelson Summer Research Scholarship.

[2019] Read our review "Recently mobilized transposons in the human genome" and collaborative work "Transposon expression and repression in human fetal germ cells".

[2018] Dr. An receives an R15 AREA grant from NIGMS.

[2018] Chase Habben receives the Schultz-Werth Paper Award.

[2018] Partha Saha receives Sigma Xi Graduate Proposal Competition 2nd Place.

[2018] Simon Newkirk receives Professional Staff Excellence in Scholarly Activity Award.

[2017] Chase Habben receives the Joseph F. Nelson Summer Research Scholarship.

[2017] Mason Jones receives the Schultz-Werth Paper Award.

[2017] Simon's PNAS paper is out. See Commentary by J.P. Wang and Highlight by C. Chen.

[2016] Mason Jones receives the Joseph F. Nelson Summer Research Scholarship.

[2016] Nicole Vanden Berg is accepted into University of Minnesota VetMed Program.

[2016] Dr. An is named the College of Pharmacy Outstanding Researcher.

[2015] Dr. An receives two R21 grants from NICHD and NIH Office of the Director.

[2015] Our Genome Research paper is now online.

[2014] We are now a member of NIGMS P50 Center for Systems Biology of Retrotransposition.

Undergraduate Student

Projects are available for motivated undergraduate students. Will work on independent projects as well as teaming with experienced graduate students and postdocs. Must be committed and have a passion for biomedical research.

Graduate Student

No current openings. Prospective students may submit pre-application inquiry to Dr. An.
Ph.D. Program and Instructions