Current lab members:

• Gael Cristofari (DR2, Inserm)
• Sabrina Sacconi (PU-PH, CHU)
• Aurélien Doucet (CRCN, CNRS)
• Sophie Lanciano (Postdoc)
• Misaki Matsuo (Postdoc)
• Victor Billon (PhD student)
• Larisa Okorokova (PhD student)
• Emanuela Repetto (IE, UniCA)
• Salomé Retailleau (Engineer)
• Humaira Choudhury (Erasmus Master Student (Univ. of Milan IT))

Lab Alumni:

One of the most surprising discoveries made by large scale genome projects – and one of their most difficult challenges – has been the abundance of repetitive DNA in eukaryotic genomes. For example, our chromosomes contain nearly 50% of DNA repeats. Remarkably, the vast majority of these sequences results from the activity of transposable elements. These mobile DNA sequences, also known as “jumping genes”, can multiply and/or disperse by cut-and-paste or copy-and-paste mechanisms. Our main objectives are to understand how transposable elements contribute to the plasticity of the human genome and epigenome, and what are their consequences at the molecular, cellular and physiological levels. Our lab combines biochemistry, molecular and cellular biology, genome engineering, genomics and bioinformatics to address these questions.

In humans, the only active and autonomous transposable element family is a group of retrotransposons of the LINE-1 (L1) clade, named L1HS and unique to the human lineage. Thus, we mostly focused our work on this family. Each individual has hundreds of L1HS copies absent from the reference genome (polymorphic L1 insertions), which contribute to our genetic diversity. L1HS is not only able to mobilize in the germline – resulting in inheritable genetic variations, and occasionally in genetic disease – but can also be active in some somatic tissues, such as the brain, in many epithelial cancers, and during normal or pathological aging.

The strength and originality of our research lies in our ability to study transposable elements at the level of individual copies. A central aspect of this work has been the development of ATLAS-seq, a deep-sequencing approach to comprehensively map the position of L1 elements in individual human genomes, as well as variation of this technique to assess the DNA methylation level of each L1 copy genome-wide. More recently, we leveraged nanopore sequencing with ultra-long reads, as well as CRISPR-Cas9 genome and epigenome editing, to study L1-mediated genome and epigenome variations.

Current Projects

Top Publications

• LINE-1, the NORth star of nucleolar organization
  10 janvier 2025 par Misaki Matsuo
  Long interspersed element-1 (LINE-1) retrotransposons are abundant transposable elements in mammals and significantly influence chromosome structure, chromatin organization, and 3D genome architecture. In this issue of Genes & Development, Ataei et al. (doi:10.1101/gad.351979.124) identify a homininae-specific LINE-1 element within nucleolar ogranizer regions (NORs) that is specifically transcribed in naïve human embryonic stem cells. Deletion or silencing of this element disrupts nucleolar…
• International congress on transposable elements (ICTE 2024) in Saint Malo: breaking down transposon waves and their impact
  27 octobre 2024 par Pascale Lesage
  From April 20 to 23, 2024, three hundred ten researchers from around the world gathered in Saint-Malo, France, at the fourth International Congress on Transposable Elements (ICTE 2024), to present their most recent discoveries on transposable elements (TEs) and exchange ideas and methodologies. ICTE has been held every four years since 2008 (except in 2020, when it was exceptionally transformed into a seminar series due to the Covid-19 pandemic) and is organized by the French network on Mobile…
• A novel bioinformatic approach reveals cooperation between Cancer/Testis genes in basal-like breast tumors
  12 mars 2024 par Marthe Laisné
  Breast cancer is the most prevalent type of cancer in women worldwide. Within breast tumors, the basal-like subtype has the worst prognosis, prompting the need for new tools to understand, detect, and treat these tumors. Certain germline-restricted genes show aberrant expression in tumors and are known as Cancer/Testis genes; their misexpression has diagnostic and therapeutic applications. Here we designed a new bioinformatic approach to examine Cancer/Testis gene misexpression in breast tumors….
• Locus-level L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites
  3 février 2024 par Sophie Lanciano
  Long interspersed element 1 (L1) retrotransposons are implicated in human disease and evolution. Their global activity is repressed by DNA methylation, but deciphering the regulation of individual copies has been challenging. Here, we combine short- and long-read sequencing to unveil L1 methylation heterogeneity across cell types, families, and individual loci and elucidate key principles involved. We find that the youngest primate L1 families are specifically hypomethylated in pluripotent stem…
• Noninvasive and Multicancer Biomarkers: The Promise of LINE-1 Retrotransposons
  12 décembre 2023 par Aurelien J Doucet
  LINE-1 retrotransposons are frequently active in epithelial tumors. In a new study, Taylor, Wu and colleagues now describe that one of the proteins encoded by LINE-1 elements, ORF1p, is detected in the bloodstream of patients with cancer, and can be used as a noninvasive and multicancer biomarker for diagnosis or treatment monitoring. See related article by Taylor, Wu et al., p. 2532 (7).
• A genetic screen identifies BEND3 as a regulator of bivalent gene expression and global DNA methylation
  31 août 2023 par Lounis Yakhou
  Epigenetic mechanisms are essential to establish and safeguard cellular identities in mammals. They dynamically regulate the expression of genes, transposable elements and higher-order chromatin structures. Consequently, these chromatin marks are indispensable for mammalian development and alterations often lead to disease, such as cancer. Bivalent promoters are especially important during differentiation and development. Here we used a genetic screen to identify new regulators of a bivalent…
• Cancer Immunotherapy: How to Exploit Transposable Elements?
  12 août 2023 par Sophie Lanciano
  No abstract
• A genome-wide screen reveals new regulators of the 2-cell-like cell state
  24 juillet 2023 par Nikhil Gupta
  In mammals, only the zygote and blastomeres of the early embryo are totipotent. This totipotency is mirrored in vitro by mouse '2-cell-like cells' (2CLCs), which appear at low frequency in cultures of embryonic stem cells (ESCs). Because totipotency is not completely understood, we carried out a genome-wide CRISPR knockout screen in mouse ESCs, searching for mutants that reactivate the expression of Dazl, a gene expressed in 2CLCs. Here we report the identification of four mutants that…
• Genome-Wide Young L1 Methylation Profiling by bs-ATLAS-seq
  30 novembre 2022 par Claude Philippe
  By silencing L1 retrotransposons, DNA methylation protects mammalian genomes from potent endogenous mutagens. However, some loci can escape this repressive mechanism and become active, particularly in carcinomas. Alterations of L1 DNA methylation can also locally influence gene expression. Comprehensive measurement of L1 DNA methylation at the locus level remains challenging. Here, we present bs-ATLAS-seq, a genome-wide approach to locate full-length L1 elements in the human genome, and assess…
• Targeted Nanopore Resequencing and Methylation Analysis of LINE-1 Retrotransposons
  30 novembre 2022 par Arpita Sarkar
  Retrotransposition of LINE-1 (L1) elements represents a major source of insertional polymorphisms in mammals, and their mutagenic activity is restricted by silencing mechanisms, such as DNA methylation. Despite a very high level of sequence identity between copies, their internal sequence contains small nucleotide polymorphisms (SNPs) that can alter their activity. Such internal SNPs can also appear in different alleles of a given L1 locus. Given their repetitive nature and relatively long size,…
• Precise and Scarless Insertion of Transposable Elements by Cas9-Mediated Genome Engineering
  30 novembre 2022 par Vivien Marie Weber
  Transposable element insertions can have broad effects on gene expression, ranging from new regulatory functions to pathogenic consequences by transplanting new cis-regulating elements or perturbing existing ones. Genetic manipulation of such DNA sequences can help decipher their mechanism of action. Here, we describe a CRISPR-Cas9-mediated two-step approach to precisely insert transposable elements into into the genome of cultured human cells, without scar or reporter gene. First, a…
• Flip-flop genomics: Charting inversions in the human population
  27 mai 2022 par Sophie Lanciano
  Detecting large genomic inversions has long been challenging. In a new study, Porubsky et al. resolve these complex rearrangements in 41 individuals and discover wide regions that undergo recurrent inversions, some of which even toggle back and forth (Porubsky et al., 2022). Many of these regions are associated with genomic disorders.
• TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV
  11 janvier 2022 par Roy Matkovic
  The Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin recruits the histone methyl-transferase SETDB1 to spread H3K9me3 repressive marks across genes and transgenes in an integration site-dependent manner. The deposition of these repressive marks leads to heterochromatin formation and inhibits gene expression, but the underlying mechanism is not fully understood. Here, we show that TASOR silencing or HIV-2 Vpx expression, which induces TASOR degradation, increases the…
• Locus-specific chromatin profiling of evolutionarily young transposable elements
  15 décembre 2021 par Darren Taylor
  Despite a vast expansion in the availability of epigenomic data, our knowledge of the chromatin landscape at interspersed repeats remains highly limited by difficulties in mapping short-read sequencing data to these regions. In particular, little is known about the locus-specific regulation of evolutionarily young transposable elements (TEs), which have been implicated in genome stability, gene regulation and innate immunity in a variety of developmental and disease contexts. Here we propose an…
• Nascent RNA m⁶A modification at the heart of the gene-retrotransposon conflict
  10 juin 2021 par Victor Billon
  No abstract
• The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition
  12 novembre 2020 par Pablo Tristán-Ramos
  Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently…
• Measuring and interpreting transposable element expression
  25 juin 2020 par Sophie Lanciano
  Transposable elements (TEs) are insertional mutagens that contribute greatly to the plasticity of eukaryotic genomes, influencing the evolution and adaptation of species as well as physiology or disease in individuals. Measuring TE expression helps to understand not only when and where TE mobilization can occur but also how this process alters gene expression, chromatin accessibility or cellular signalling pathways. Although genome-wide gene expression assays such as RNA sequencing include…
• The Landscape of L1 Retrotransposons in the Human Genome Is Shaped by Pre-insertion Sequence Biases and Post-insertion Selection
  9 avril 2019 par Tania Sultana
  L1 retrotransposons are transposable elements and major contributors of genetic variation in humans. Where L1 integrates into the genome can directly impact human evolution and disease. Here, we experimentally induced L1 retrotransposition in cells and mapped integration sites at nucleotide resolution. At local scales, L1 integration is mostly restricted by genome sequence biases and the specificity of the L1 machinery. At regional scales, L1 shows a broad capacity for integration into all…
• The OncoAge Consortium: Linking Aging and Oncology from Bench to Bedside and Back Again
  24 février 2019 par Paul Hofman
  It is generally accepted that carcinogenesis and aging are two biological processes, which are known to be associated. Notably, the frequency of certain cancers (including lung cancer), increases significantly with the age of patients and there is now a wealth of data showing that multiple mechanisms leading to malignant transformation and to aging are interconnected, defining the so-called common biology of aging and cancer. OncoAge, a consortium launched in 2015, brings together the…
• Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome
  29 juillet 2018 par Dimitri Renard
  Facioscapulohumeral muscular dystrophy (FSHD) has been shown to be related to genetic and epigenetic derepression of DUX4 (mapping to chromosome 4), a gene located within a repeat array of D4Z4 sequences of polymorphic length. FSHD type 1 (FSHD1) is associated with pathogenic D4Z4 repeat array contraction, while FSHD type 2 (FSHD2) is associated with SMCHD1 variants (a chromatin modifier gene that maps to the short arm of chromosome 18). Both FSHD types require permissive polyadenylation signal…

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