Dr Carreira has a long standing interest in mobile elements. Her first research contact with mobile elements was within the molecular medicine post-graduate program at the University of Santiago de Compostela, Spain. During this program, her research was focused on developing scripts to annotate mobile elements in the Drosophila simulans genome. This experience encouraged her to further study mobile elements.
Dr Carreira obtained her PhD from the University of Granada, Spain, identifying mobile elements’ sequences with transcription and/or ribozime activity in Trypanosoma brucei , thanks to a scholarship from the Spanish Government (FPI program).
Since Dr Carreira joined Prof. Faulkner’s lab, she has been focused on the implications of human L1 activity in cancer.
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)
In: Molecular Cell, 0 (0), 2019, ISSN: 1097-2765.
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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
Nguyen, Thu H M; Carreira, Patricia E; Sanchez-Luque, Francisco J; Schauer, Stephanie N; Fagg, Allister C; Richardson, Sandra R; Davies, Claire M; Jesuadian, Samuel J; Kempen, Marie-Jeanne H C; Troskie, Robin-Lee; James, Cini; Beaven, Elizabeth A; Wallis, Tristan P; Coward, Jermaine I G; Chetty, Naven P; Crandon, Alexander J; Venter, Deon J; Armes, Jane E; Perrin, Lewis C; Hooper, John D; Ewing, Adam D; Upton, Kyle R; Faulkner, Geoffrey J
L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution (Journal Article)
In: Cell Reports, 23 (13), pp. 3730–3740, 2018, ISSN: 2211-1247.
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LINE-1 (L1) retrotransposons are a source of insertional mutagenesis in tumor cells. However, the clinical significance of L1 mobilization during tumorigenesis remains unclear. Here, we applied retrotransposon capture sequencing (RC-seq) to multiple single-cell clones isolated from five ovarian cancer cell lines and HeLa cells and detected endogenous L1 retrotransposition in vitro. We then applied RC-seq to ovarian tumor and matched blood samples from 19 patients and identified 88 tumor-specific L1 insertions. In one tumor, an intronic de novo L1 insertion supplied a novel cis-enhancer to the putative chemoresistance gene STC1. Notably, the tumor subclone carrying the STC1 L1 mutation increased in prevalence after chemotherapy, further increasing STC1 expression. We also identified hypomethylated donor L1s responsible for new L1 insertions in tumors and cultivated cancer cells. These congruent in vitro and in vivo results highlight L1 insertional mutagenesis as a common component of ovarian tumorigenesis and cancer genome heterogeneity.
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
In: Genome Research, 2018, ISSN: 1088-9051, 1549-5469.
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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.
Richardson, Sandra R; Gerdes, Patricia; Gerhardt, Daniel J; Sanchez-Luque, Francisco J; Bodea, Gabriela-Oana; noz-Lopez, Martin Mu; Jesuadian, Samuel J; Kempen, Marie-Jeanne H C; Carreira, Patricia E; Jeddeloh, Jeffrey A; Garcia-Perez, Jose L; Jr, Haig H Kazazian; Ewing, Adam D; Faulkner, Geoffrey J
In: Genome Res., 27 (8), pp. 1395–1405, 2017.
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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.
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
In: Mob. DNA, 7 (1), pp. 21, 2016.
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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.
Carreira, Patricia E; Richardson, Sandra R; Faulkner, Geoffrey J
L1 retrotransposons, cancer stem cells and oncogenesis (Journal Article)
In: FEBS J., 281 (1), pp. 63–73, 2014.
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Retrotransposons have played a central role in human genome
evolution. The accumulation of heritable L1, Alu and SVA
retrotransposon insertions continues to generate structural
variation within and between populations, and can result in
spontaneous genetic disease. Recent works have reported
somatic L1 retrotransposition in tumours, which in some cases
may contribute to oncogenesis. Intriguingly, L1 mobilization
appears to occur almost exclusively in cancers of epithelial
cell origin. In this review, we discuss how L1
retrotransposition could potentially trigger neoplastic
transformation, based on the established correlation between
L1 activity and cellular plasticity, and the proven capacity
of L1-mediated insertional mutagenesis to decisively alter
gene expression and functional output.
Sánchez-Luque, Francisco José; López, Manuel Carlos; Carreira, Patricia Eugenia; Alonso, Carlos; Thomas, María Carmen
In: BMC genomics, 15 , pp. 340, 2014, ISSN: 1471-2164.
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BACKGROUND: Hepatitis Delta Virus (HDV)-like ribozymes have recently been found in many mobile elements in which they take part in a mechanism that releases intermediate RNAs from cellular co-transcripts. L1Tc in Trypanosoma cruzi is one of the elements in which such a ribozyme is located. It lies in the so-called Pr77-hallmark, a conserved region shared by retrotransposons belonging to the trypanosomatid L1Tc/ingi clade. The wide distribution of the Pr77-hallmark detected in trypanosomatid retrotransposons renders the potential catalytic activity of these elements worthy of study: their distribution might contribute to host genetic regulation at the mRNA level. Indeed, in Leishmania spp, the pervasive presence of these HDV-like ribozyme-containing mobile elements in certain 3'-untranslated regions of protein-coding genes has been linked to mRNA downregulation.
RESULTS: Intensive screening of publicly available trypanosomatid genomes, combined with manual folding analyses, allowed the isolation of putatively Pr77-hallmarks with HDV-like ribozyme activity. This work describes the conservation of an HDV-like ribozyme structure in the Pr77 sequence of retrotransposons in a wide range of trypanosomatids, the catalytic function of which is maintained in the majority.These results are consistent with the previously suggested common phylogenetic origin of the elements that belong to this clade, although in some cases loss of functionality appears to have occurred and/or perhaps molecular domestication by the host.
CONCLUSIONS: These HDV-like ribozymes are widely distributed within retrotransposons across trypanosomatid genomes. This type of ribozyme was once thought to be rare in nature, but in fact it would seem to be abundant in trypanosomatid transcripts. It can even form part of the pool of mRNA 3'-untranslated regions, particularly in Leishmania spp. Its putative regulatory role in host genetic expression is discussed.
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