November 16, 2022

Transposable Elements as Cancer Biomarkers and Therapeutic Targets

1st Call, Tech Trans

Short Summary

Our genome contains a vast amount of virus-related sequences. Over 4 million fragments of our DNA derive from mobile genetic elements, some of which once were viruses that infected the germ line of our ancestors. These transposable elements (TEs) outnumber genes by two orders of magnitude (> 4 million versus ~25’000 genes). It has recently come to the fore that, a fraction of them are still transcriptionally active in adult tissues and provide unique molecular signatures, high density “barcodes” of cellular states in health and disease. This opens up the prospect of identifying novel, uncharted RNA biomarkers in a huge pool of elements spanning up to 80% of the genome (in comparison to 1.5% for protein coding genes) with broad applications in precision oncology.

Goals

The present proposal aims at capitalizing on these preliminary data and on our analytical know- how to join forces with computer scientists of the Swiss Data Science Center and with clinicians involved in cancer care in order to mature TE-targeting technology (TETT) into a pillar of personalized health and individualized management in the field of oncology.

Significance

Specifically, we plan to demonstrate that TETT-generated TE-derived-information (TEDI) is particularly well suited to obtain cancer biomarkers that display high specificity, sensitivity, robustness and precision for the assignment of cancer cells to specific subcategories, whether tissue of origin, tumor type, tumor stage, predicted response to therapy. Owing to their abundance in the genome and largely uncharted status, TEs provide a unique opportunity for diagnostics. In addition, we believe TEDI will open crucial novel therapeutic avenues in oncology. Indeed, TEs represent a unique source of targets for both pharmacological treatment of cancer and immunotherapy through identification of neo- antigens. This project will thus serve as seed for the establishment of TETT as a certified technology, paving the way to its industrialization and broad utilization in precision medicine and individualized management in the field of cancer.

Background

Transposable elements (TEs) may contribute up to 80% of the human genome. Long considered as junk DNA, this so-called endovirome is now recognized as an essential motor of evolution. Over the last few years, we developed a leading expertise in the extraction and analysis of TE-derived information (TEDI). This allowed us to uncover that tens of thousands of TE loci are expressed in all examined human tissues, from embryonic stem cells to terminally differentiated neurons, that they are under exquisite control by a large family of developmental stage- and tissue-restricted modulators, and that they exert profound regulatory influences on the expression of cellular genes. We further determined that the sum of TE-derived transcripts, which we coined the transposcriptome, provides a high-density barcode for cell identity, differentiation level and activation status, with a far greater precision that its gene-based counterpart. Turning to cancer, we obtained data indicating that TEDI can be an unmatched source of biomarkers and specific neo-antigens for targeting by immunotherapy.

Publications

A Dissection of Oligomerization by the TRIM28 Tripartite Motif and the Interaction with Members of the Krab-ZFP Family Y. Sun; J. R. Keown; M. M. Black; C. Raclot; N. Demarais et al. Journal of Molecular Biology. 2019-06-28. Vol. 431, num. 14, p. 2511-2527. DOI : 10.1016/j.jmb.2019.05.002.
DPPA2 and DPPA4 are necessary to establish a 2C‐like state in mouse embryonic stem cells A. De Iaco; A. Coudray; J. Duc; D. Trono EMBO reports. 2019-04-04. p. e47382. DOI : 10.15252/embr.201847382.
DUX is a non-essential synchronizer of zygotic genome activation A. De Iaco; S. Verp; S. Offner; D. Grun; D. Trono Development. 2019-12-05. p. dev.177725. DOI : 10.1242/dev.177725.
Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression J. Ito; I. Kimura; A. Soper; A. Coudray; Y. Koyanagi et al. Science Advances. 2020-10-01. Vol. 6, num. 43, p. eabc3020. DOI : 10.1126/sciadv.abc3020.
HIV-1 Vpr and p21 restrict LINE-1 mobility K. Kawano; A. J. Doucet; M. Ueno; R. Kariya; W. An et al. Nucleic Acids Research. 2018-07-31. Vol. 46, num. 16, p. 8454-8470. DOI : 10.1093/nar/gky688.
Hominoid-Specific Transposable Elements and KZFPs Facilitate Human Embryonic Genome Activation and Control Transcription in Naive Human ESCs J. Pontis; E. Planet; S. Offner; P. Turelli; J. Duc et al. Cell Stem Cell. 2019-03-27. Vol. 24, num. 5, p. 724-735. DOI : 10.1016/j.stem.2019.03.012.
Individual retrotransposon integrants are differentially controlled by KZFP/KAP1-dependent histone methylation, DNA methylation and TET-mediated hydroxymethylation in naïve embryonic stem cells A. Coluccio; G. Ecco; J. Duc; S. Offner; P. Turelli et al. Epigenetics & Chromatin. 2018-02-26. Vol. 11, num. 1, p. 7. DOI : 10.1186/s13072-018-0177
Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes C. Chong; M. Müller; H. Pak; D. Harnett; F. Huber et al. Nature Communications. 2020-03-10. Vol. 11, num. 1239. DOI : 10.1038/s41467-020-14968-9.
KAP1 facilitates reinstatement of heterochromatin after DNA replication S. M. Jang; A. Kauzlaric; J-P. Quivy; J. Pontis; B. Rauwel et al. Final Scientific Report 6 Nucleic Acids Research. 2018-06-28. Vol. 46, num. 17, p. 8788-8802. DOI : 10.1093/nar/gky580.
KAP1 is an antiparallel dimer with a functional asymmetry G. Fonti; M. J. Marcaida; L. C. Bryan; S. Traeger; A. S. Kalantzi et al. Life Science Alliance. 2019-08-01. Vol. 2, num. 4, p. e201900349. DOI : 10.26508/lsa.201900349.
KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA polymerase II activity. A. Kauzlaric; S. M. Jang; M. Morchikh; M. Cassano; E. Planet et al. Philosophical Transactions of the Royal Society B: Biological Sciences. 2020-02-10. Vol. 375, num. 1795, p. 20190334. DOI : 10.1098/rstb.2019.0334.
KRAB-zinc finger protein gene expansion in response to active retrotransposons in the murine lineage G. Wolf; A. de Iaco; M-A. Sun; M. Bruno; M. Tinkham et al. e Life. 2020-06-01. Vol. 9, num. e56337. DOI : 10.7554/eLife.56337. Final Scientific Report 5
Pharmacological induction of a progenitor state for the efficient expansion of primary human hepatocytes C. Unzu; E. Planet; N. Brandenberg; F. Fusil; M. Cassano et al. 2018-12-14. DOI : 10.1002/hep.30425.
Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons . Turelli; C. Playfoot; D. Grun; C. Raclot; J. Pontis et al. Science Advances. 2020-08-28. Vol. 6, num. 35, p. eaba3200. DOI:10.1126/sciadv.aba3200
Properties of LINE-1 proteins and repeat element expression in the context of amyotrophic lateral sclerosis G. C. Pereira; L. Sanchez; P. M. Schaughency; A. Rubio-Roldan; J. A. Choi et al. Mobile Dna. 2018-12-15. Vol. 9, p. 35. DOI : 10.1186/s13100-018-0138-z.
The Human RNA Helicase DDX21 Presents a Dimerization Interface Necessary for Helicase Activity M. J. Marcaida Lopez; A. Kauzlaric; A. Duperrex; J. Sülzle; M. C. Moncrieffe et al. iScience. 2020-11-18. Vol. 23, num. 12, p. 101811. DOI : 10.1016/j.isci.2020.101811.
The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification P. Helleboid; M. Heusel; J. Duc; C. Piot; C. W. Thorball et al. The EMBO Journal. 2019-08-12. p. 1-16. DOI : 10.15252/embj.2018101220.
ZFP30 promotes adipogenesis through the KAP1-mediated activation of a retrotransposon-derived Pparg2 enhancer W. Chen; P. C. Schwalie; E. V. Pankevich; C. Gubelmann; S. K. Raghav et al. Nature Communications. 2019-04-18. Vol. 10, num. 1. DOI : 10.1038/s41467-019-09803-9.
ZNF445 is a primary regulator of genomic imprinting N. Takahashi; A. Coluccio; C. W. Thorball; E. Planet; H. Shi et al. Genes & Development. 2019-01-01. Vol. 33, num. 1-2, p. 49-54. DOI : 10.1101/gad.320069.118.