Email: Gael.Cristofari[at]ens-lyon.fr
Tel: +33 (0)4 72 72 80 51
Fax: +33 (0)4 72 72 81 37

Overview

The abundance of transposable elements in the human genome was one of the most surprising and disconcerting discoveries of genomics. More than 40% of our DNA is made of mobile genetic elements, also called “jumping genes”. Human retrotransposons (LINE-1 and Alu) and human endogenous retroviruses (HERVs) are highly repetitive and dispersed sequences, which account for half of our DNA. They can proliferate through an RNA-mediated copy-and-paste mechanism, called retrotransposition. This process has similarities to the replication of retroviruses. Endogenous retroelements are transmitted by mendelian inheritance and are, most of the time, restricted to the host cell.

Nevertheless they can influence the infection by exogenous retroviruses. Sequences derived from ancient retroelements offer an innate genetic protection against the invasion by new endogenous or exogenous retroelements and have been fixed in mammalian genomes (Fv genes, piRNAs, siRNAs). Common cellular pathways limit both the replication of endogenous retroelements and the infection by exogenous retroviruses (APOBEC3 and TRIM families). Inversely defective exo- and endogenous retroviruses can cooperate or even recombine, resulting in the emergence of infectious and replicative viral strains. Interestingly endogenous retroviruses provide fingerprints of ancient exogenous infections allowing us to study the co-evolution of retroviruses and host genomes.

Endogenous retroelements also play a fundamental role in the current evolution and plasticity of the human genome and can result in the appearance of new genetic diseases or in tumorigenesis. However the importance and consequences of retrotransposition on human health have been poorly studied, mostly due to difficulties in tracking new insertion events in clinical samples. Indeed it is extremely difficult to detect a new copy in a new locus among the hundreds of thousands copies inherited from our parents.

Projects

Our research interests are focused:

• on the discovery of cellular pathways that control the copy number of retrotransposons and their effect on exogenous retrovirus replication ;
  
• on dissecting the molecular mechanisms of retrotransposition in comparison to retrovirus replication ;
  
• on understanding how endogenous retroelements can participate in the normal and pathological remodeling of the human genome, in particular in human cancers ;
  
• on the development of innovative bioinformatics approaches to systematically discover, annotate and analyze endogenous retroviral sequences from full genome sequences and to study the co-evolution of retroviruses and their hosts.

Understanding how the activity of retrotransposons and endogenous retroviruses is controlled will impact our knowledge of virus-host interactions and of the mechanisms that lead to new genetic diseases or to cancer progression. Since mobile genetic elements are becoming important tools in insertional mutagenesis or gene-transfer technologies in mammals, our work should also help to improve and widen the use of retrotransposons in mammalian functional genomics or gene-therapy.

Recent Selected Publications

• Kurth I, Cristofari G, Lingner J. (2008) An affinity oligonucleotide displacement strategy to purify ribonucleoprotein complexes applied to human telomerase. Methods Mol Biol. 488:9-22. [Abstract] [PubMed]
• De Cian A, Cristofari G, Reichenbach P, Delemos E, Monchaud D, Teulade-Fichou MP, Shin-ya K, Lacroix L, Lingner J, & Mergny JL. (2007) Re-evaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action. Proc. Natl Acad. Sci. USA. 104(44):17347-17352. [Abstract] [Full Text] [PDF] [PubMed]
• Cristofari G, Reichenbach P, Regamey PO, Banfi D, Chambon M, Turcatti G, Lingner J. (2007) Low- to high-throughput analysis of telomerase modulators with Telospot. Nat. Methods. 4(10):851-853. [Abstract] [PubMed]

• Cristofari G, Adolf E, Reichenbach P, Sikora K, Terns RM, Terns MP, Lingner J. (2007) Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation. Mol. Cell. 27(6):882-889. [Abstract] [PubMed]
• Cristofari G, Lingner J. (2006) Telomere length homeostasis requires that telomerase levels are limiting. EMBO J.  25(3):565-74. [Abstract] [Full Text] [PDF] [PubMed]
• Cristofari G, Bampi C, Wilhelm M, Wilhelm FX, Darlix JL. (2002) A 5'-3' long-range interaction in Ty1 RNA controls its reverse transcription and retrotransposition. EMBO J. 21(16):4368-79. [Full Text] [PDF] [PubMed]
• Cristofari G, Darlix JL. (2002) The ubiquitous nature of RNA chaperone proteins. Prog Nucleic Acid Res. Mol. Biol. 72:223-68. [Abstract] [PDF] [PubMed]

PubMed List of all Cristofari Publications