Biography

Research Links:
Publications:
2019 | |
Sanchez-Luque, Francisco J; Kempen, Marie-Jeanne H C; Gerdes, Patricia; Vargas-Landin, Dulce B; Richardson, Sandra R; Troskie, Robin-Lee; Jesuadian, Samuel J; Cheetham, Seth W; Carreira, Patricia E; Salvador-Palomeque, Carmen; García-Cañadas, Marta; Muñoz-Lopez, Martin; Sanchez, Laura; Lundberg, Mischa; Macia, Angela; Heras, Sara R; Brennan, Paul M; Lister, Ryan; Garcia-Perez, Jose L; Ewing, Adam D; Faulkner, Geoffrey J LINE-1 Evasion of Epigenetic Repression in Humans (Journal Article) Molecular Cell, 0 (0), 2019, ISSN: 1097-2765. (Abstract | Links | BibTeX | Altmetric) @article{sanchez-luque_line-1_2019, title = {LINE-1 Evasion of Epigenetic Repression in Humans}, author = {Francisco J Sanchez-Luque and Marie-Jeanne H C Kempen and Patricia Gerdes and Dulce B Vargas-Landin and Sandra R Richardson and Robin-Lee Troskie and Samuel J Jesuadian and Seth W Cheetham and Patricia E Carreira and Carmen Salvador-Palomeque and Marta Garc\'{i}a-Ca\~{n}adas and Martin Mu\~{n}oz-Lopez and Laura Sanchez and Mischa Lundberg and Angela Macia and Sara R Heras and Paul M Brennan and Ryan Lister and Jose L Garcia-Perez and Adam D Ewing and Geoffrey J Faulkner}, url = {https://www.cell.com/molecular-cell/abstract/S1097-2765(19)30396-X}, doi = {10.1016/j.molcel.2019.05.024}, issn = {1097-2765}, year = {2019}, date = {2019-01-01}, urldate = {2019-06-24}, journal = {Molecular Cell}, volume = {0}, number = {0}, abstract = {textlessh2textgreaterSummarytextless/h2textgreatertextlessptextgreaterEpigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3ʹ transduction. The source (donor) L1 for this insertion was slightly 5ʹ truncated, lacked the YY1 binding site, and was highly mobile when tested textitin vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body.textless/ptextgreater}, keywords = {}, pubstate = {published}, tppubtype = {article} } textlessh2textgreaterSummarytextless/h2textgreatertextlessptextgreaterEpigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3ʹ transduction. The source (donor) L1 for this insertion was slightly 5ʹ truncated, lacked the YY1 binding site, and was highly mobile when tested textitin vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body.textless/ptextgreater | |
2018 | |
Schauer, Stephanie N; Carreira, Patricia E; Shukla, Ruchi; Gerhardt, Daniel J; Gerdes, Patricia; Sanchez-Luque, Francisco J; Nicoli, Paola; Kindlova, Michaela; Ghisletti, Serena; Santos, Alexandre Dos; Rapoud, Delphine; Samuel, Didier; Faivre, Jamila; Ewing, Adam D; Richardson, Sandra R; Faulkner, Geoffrey J L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis (Journal Article) Genome Research, 2018, ISSN: 1088-9051, 1549-5469. (Abstract | Links | BibTeX | Altmetric) @article{schauer_l1_2018, title = {L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis}, author = {Stephanie N Schauer and Patricia E Carreira and Ruchi Shukla and Daniel J Gerhardt and Patricia Gerdes and Francisco J Sanchez-Luque and Paola Nicoli and Michaela Kindlova and Serena Ghisletti and Alexandre Dos Santos and Delphine Rapoud and Didier Samuel and Jamila Faivre and Adam D Ewing and Sandra R Richardson and Geoffrey J Faulkner}, url = {http://genome.cshlp.org/content/early/2018/04/11/gr.226993.117}, doi = {10.1101/gr.226993.117}, issn = {1088-9051, 1549-5469}, year = {2018}, date = {2018-01-01}, urldate = {2018-08-28}, journal = {Genome Research}, abstract = {The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)−/− mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including TF subfamily elements, and one GF subfamily example. One of the TF insertions carried a 3′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length TF element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)−/− mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including TF subfamily elements, and one GF subfamily example. One of the TF insertions carried a 3′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length TF element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors. | |
2017 | |
Richardson, Sandra R; Gerdes, Patricia; Gerhardt, Daniel J; Sanchez-Luque, Francisco J; Bodea, Gabriela-Oana; ~n, Martin Mu; Jesuadian, Samuel J; Kempen, Marie-Jeanne H C; Carreira, Patricia E; Jeddeloh, Jeffrey A; Garcia-Perez, Jose L; Jr, Haig Kazazian H; Ewing, Adam D; Faulkner, Geoffrey J Heritable L1 retrotransposition in the mouse primordial germline and early embryo (Journal Article) Genome Res., 27 (8), pp. 1395–1405, 2017. @article{Richardson2017-hr, title = {Heritable L1 retrotransposition in the mouse primordial germline and early embryo}, author = {Sandra R Richardson and Patricia Gerdes and Daniel J Gerhardt and Francisco J Sanchez-Luque and Gabriela-Oana Bodea and Martin Mu{~n}oz-Lopez and Samuel J Jesuadian and Marie-Jeanne H C Kempen and Patricia E Carreira and Jeffrey A Jeddeloh and Jose L Garcia-Perez and Haig H Kazazian Jr and Adam D Ewing and Geoffrey J Faulkner}, url = {http://dx.doi.org/10.1101/gr.219022.116}, year = {2017}, date = {2017-08-01}, journal = {Genome Res.}, volume = {27}, number = {8}, pages = {1395--1405}, abstract = {LINE-1 (L1) retrotransposons are a noted source of genetic diversity and disease in mammals. To expand its genomic footprint, L1 must mobilize in cells that will contribute their genetic material to subsequent generations. Heritable L1 insertions may therefore arise in germ cells and in pluripotent embryonic cells, prior to germline specification, yet the frequency and predominant developmental timing of such events remain unclear. Here, we applied mouse retrotransposon capture sequencing (mRC-seq) and whole-genome sequencing (WGS) to pedigrees of C57BL/6J animals, and uncovered an L1 insertion rate of $geq$1 event per eight births. We traced heritable L1 insertions to pluripotent embryonic cells and, strikingly, to early primordial germ cells (PGCs). New L1 insertions bore structural hallmarks of target-site primed reverse transcription (TPRT) and mobilized efficiently in a cultured cell retrotransposition assay. Together, our results highlight the rate and evolutionary impact of heritable L1 retrotransposition and reveal retrotransposition-mediated genomic diversification as a fundamental property of pluripotent embryonic cells in vivo.}, keywords = {}, pubstate = {published}, tppubtype = {article} } LINE-1 (L1) retrotransposons are a noted source of genetic diversity and disease in mammals. To expand its genomic footprint, L1 must mobilize in cells that will contribute their genetic material to subsequent generations. Heritable L1 insertions may therefore arise in germ cells and in pluripotent embryonic cells, prior to germline specification, yet the frequency and predominant developmental timing of such events remain unclear. Here, we applied mouse retrotransposon capture sequencing (mRC-seq) and whole-genome sequencing (WGS) to pedigrees of C57BL/6J animals, and uncovered an L1 insertion rate of $geq$1 event per eight births. We traced heritable L1 insertions to pluripotent embryonic cells and, strikingly, to early primordial germ cells (PGCs). New L1 insertions bore structural hallmarks of target-site primed reverse transcription (TPRT) and mobilized efficiently in a cultured cell retrotransposition assay. Together, our results highlight the rate and evolutionary impact of heritable L1 retrotransposition and reveal retrotransposition-mediated genomic diversification as a fundamental property of pluripotent embryonic cells in vivo. | |
2016 | |
Gerdes, Patricia; Richardson, Sandra R; Mager, Dixie L; Faulkner, Geoffrey J Transposable elements in the mammalian embryo: pioneers surviving through stealth and service (Journal Article) Genome Biol., 17 , pp. 100, 2016. @article{Gerdes2016-yk, title = {Transposable elements in the mammalian embryo: pioneers surviving through stealth and service}, author = {Patricia Gerdes and Sandra R Richardson and Dixie L Mager and Geoffrey J Faulkner}, url = {http://dx.doi.org/10.1186/s13059-016-0965-5}, year = {2016}, date = {2016-05-01}, journal = {Genome Biol.}, volume = {17}, pages = {100}, abstract = {Transposable elements (TEs) are notable drivers of genetic innovation. Over evolutionary time, TE insertions can supply new promoter, enhancer, and insulator elements to protein-coding genes and establish novel, species-specific gene regulatory networks. Conversely, ongoing TE-driven insertional mutagenesis, nonhomologous recombination, and other potentially deleterious processes can cause sporadic disease by disrupting genome integrity or inducing abrupt gene expression changes. Here, we discuss recent evidence suggesting that TEs may contribute regulatory innovation to mammalian embryonic and pluripotent states as a means to ward off complete repression by their host genome.}, keywords = {}, pubstate = {}, tppubtype = {article} } Transposable elements (TEs) are notable drivers of genetic innovation. Over evolutionary time, TE insertions can supply new promoter, enhancer, and insulator elements to protein-coding genes and establish novel, species-specific gene regulatory networks. Conversely, ongoing TE-driven insertional mutagenesis, nonhomologous recombination, and other potentially deleterious processes can cause sporadic disease by disrupting genome integrity or inducing abrupt gene expression changes. Here, we discuss recent evidence suggesting that TEs may contribute regulatory innovation to mammalian embryonic and pluripotent states as a means to ward off complete repression by their host genome. | |
Gerdes, Patricia; Richardson, Sandra R; Faulkner, Geoffrey J TET enzymes: double agents in the transposable element-host genome conflict (Journal Article) Genome Biol., 17 (1), pp. 259, 2016. @article{Gerdes2016-ga, title = {TET enzymes: double agents in the transposable element-host genome conflict}, author = {Patricia Gerdes and Sandra R Richardson and Geoffrey J Faulkner}, url = {http://dx.doi.org/10.1186/s13059-016-1124-8}, year = {2016}, date = {2016-01-01}, journal = {Genome Biol.}, volume = {17}, number = {1}, pages = {259}, abstract = {The mouse genome is replete with retrotransposon sequences, from evolutionarily young elements with mutagenic potential that must be controlled, to inactive molecular fossils whose sequences can be domesticated over evolutionary time to benefit the host genome. In an exciting new study, de la Rica and colleagues have uncovered a complex relationship between ten-eleven translocation (TET) proteins and retrotransposons in mouse embryonic stem cells (ESCs), implicating TETs as enhancers in the exaptation and function of retroelement sequences. Furthermore, they have demonstrated that active demethylation of retrotransposons does not correlate with their increased expression in ESCs, calling into question long-held assumptions regarding the importance of DNA demethylation for retrotransposon expression, and revealing novel epigenetic players in retrotransposon control.Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1096-8.}, keywords = {}, pubstate = {}, tppubtype = {article} } The mouse genome is replete with retrotransposon sequences, from evolutionarily young elements with mutagenic potential that must be controlled, to inactive molecular fossils whose sequences can be domesticated over evolutionary time to benefit the host genome. In an exciting new study, de la Rica and colleagues have uncovered a complex relationship between ten-eleven translocation (TET) proteins and retrotransposons in mouse embryonic stem cells (ESCs), implicating TETs as enhancers in the exaptation and function of retroelement sequences. Furthermore, they have demonstrated that active demethylation of retrotransposons does not correlate with their increased expression in ESCs, calling into question long-held assumptions regarding the importance of DNA demethylation for retrotransposon expression, and revealing novel epigenetic players in retrotransposon control.Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1096-8. | |
Klawitter, Sabine; Fuchs, Nina V; Upton, Kyle R; ~n, Martin Mu; Shukla, Ruchi; Wang, Jichang; ~n, Marta Garcia-Ca; Lopez-Ruiz, Cesar; Gerhardt, Daniel J; Sebe, Attila; Grabundzija, Ivana; Merkert, Sylvia; Gerdes, Patricia; Pulgarin, Andres J; Bock, Anja; Held, Ulrike; Witthuhn, Anett; Haase, Alexandra; Sarkadi, Balázs; Löwer, Johannes; Wolvetang, Ernst J; Martin, Ulrich; Ivics, Zoltán; Izsvák, Zsuzsanna; Garcia-Perez, Jose L; Faulkner, Geoffrey J; Schumann, Gerald G Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells (Journal Article) Nat. Commun., 7 , pp. 10286, 2016. @article{Klawitter2016-ur, title = {Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells}, author = {Sabine Klawitter and Nina V Fuchs and Kyle R Upton and Martin Mu{~n}oz-Lopez and Ruchi Shukla and Jichang Wang and Marta Garcia-Ca{~n}adas and Cesar Lopez-Ruiz and Daniel J Gerhardt and Attila Sebe and Ivana Grabundzija and Sylvia Merkert and Patricia Gerdes and Andres J Pulgarin and Anja Bock and Ulrike Held and Anett Witthuhn and Alexandra Haase and Bal\'{a}zs Sarkadi and Johannes L\"{o}wer and Ernst J Wolvetang and Ulrich Martin and Zolt\'{a}n Ivics and Zsuzsanna Izsv\'{a}k and Jose L Garcia-Perez and Geoffrey J Faulkner and Gerald G Schumann}, url = {http://dx.doi.org/10.1038/ncomms10286}, year = {2016}, date = {2016-01-01}, journal = {Nat. Commun.}, volume = {7}, pages = {10286}, abstract = {Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs. | |
Carreira, Patricia E; Ewing, Adam D; Li, Guibo; Schauer, Stephanie N; Upton, Kyle R; Fagg, Allister C; Morell, Santiago; Kindlova, Michaela; Gerdes, Patricia; Richardson, Sandra R; Li, Bo; Gerhardt, Daniel J; Wang, Jun; Brennan, Paul M; Faulkner, Geoffrey J Evidence for L1-associated DNA rearrangements and negligible L1 retrotransposition in glioblastoma multiforme (Journal Article) Mob. DNA, 7 (1), pp. 21, 2016. @article{Carreira2016-vr, title = {Evidence for L1-associated DNA rearrangements and negligible L1 retrotransposition in glioblastoma multiforme}, author = {Patricia E Carreira and Adam D Ewing and Guibo Li and Stephanie N Schauer and Kyle R Upton and Allister C Fagg and Santiago Morell and Michaela Kindlova and Patricia Gerdes and Sandra R Richardson and Bo Li and Daniel J Gerhardt and Jun Wang and Paul M Brennan and Geoffrey J Faulkner}, url = {http://dx.doi.org/10.1186/s13100-016-0076-6}, year = {2016}, date = {2016-01-01}, journal = {Mob. DNA}, volume = {7}, number = {1}, pages = {21}, abstract = {LINE-1 (L1) retrotransposons are a notable endogenous source of mutagenesis in mammals. Notably, cancer cells can support unusual L1 retrotransposition and L1-associated sequence rearrangement mechanisms following DNA damage. Recent reports suggest that L1 is mobile in epithelial tumours and neural cells but, paradoxically, not in brain cancers.}, keywords = {}, pubstate = {published}, tppubtype = {article} } LINE-1 (L1) retrotransposons are a notable endogenous source of mutagenesis in mammals. Notably, cancer cells can support unusual L1 retrotransposition and L1-associated sequence rearrangement mechanisms following DNA damage. Recent reports suggest that L1 is mobile in epithelial tumours and neural cells but, paradoxically, not in brain cancers. |
Share this:
- Click to share on Twitter (Opens in new window)
- Click to share on Facebook (Opens in new window)
- Click to share on LinkedIn (Opens in new window)
- Click to share on Skype (Opens in new window)
- Click to share on Tumblr (Opens in new window)
- Click to share on Pinterest (Opens in new window)
- Click to share on Pocket (Opens in new window)
- Click to print (Opens in new window)