CE12 - Génétique, génomique et ARN

The LINE-1 regulatory network: genome-wide impact of recent transposable elements on mammalian genic activity – ImpacTE

Jumping genes in Mammals: consequences on gene regulation

The LINE-1 regulatory network: genome-wide impact of recent transposable elements on mammalian genic activity

Context and objectives

Repetitive DNA sequences account for almost half of the human and mouse genomes. Most of them are degenerated remnants of ancient mobile genetic elements. However, a subset of evolutionary recent transposable elements, particularly those belonging to the LINE-1 (L1) retrotransposon family, actively contribute to the plasticity of modern mammalian genomes and to the diversity of individual genomes. Their insertions into new genomic locations convey multiple cis-acting DNA regulatory elements, and can attract and even drive the evolution of chromatin factors and other host proteins. Because the vast majority of these potentially active L1s map outside of exons, predicting their impact on gene expression, transcript structure and function remains challenging. Considering the growing number of evidences that link L1 elements to the regulation of normal developmental processes but also to the etiology of diseases, understanding how L1s influence gene activity genome-wide represents a timely and relevant endeavor. Here, we propose to test to which extent the youngest L1 retrotransposon families, L1-HS and L1-A, found in humans and mice, respectively, can influence gene expression at the genome-wide level. More specifically, the ImpacTE proposal will explore the impact of their 1) sequence, 2) transcription, and 3) chromatin states on gene regulation.

This will be achieved at the global level rather than at individual loci, by combining recent technological developments, such as CRISPR-mediated (epi)genome engineering in cellula and in vivo, genetic screens and chromatin capture, ultra long-read sequencing, and retrotransposon mapping, while capitalizing on the expertise of the two scientific partners in the biology and bioinformatic analysis of transposons, mouse genetics and epigenetics.

The first months of the project were spent setting up the tools and obtaining the biological material to carry out the project.

This proposal has the potential to reveal L1 insertions that alter gene expression in a cell-type- or tissue-specific manner and by which mechanisms they do so. Moreover, by relying on two mammalian representatives, mouse and human, and by including information from the cellular to the organismal level, we will gain complementary insights into the universal principles and specificities of the impact of L1s on mammalian genome regulation. Ultimately, our work will establish a rational basis for predicting the potential impact of thousands of retrotransposon copies identified in sequencing projects, as well as broaden our understanding of their role in the evolution of regulatory networks and novel protein functions in mammals.

Billon V, Cristofari G. Nascent RNA m6A methylation at the heart of the gene- retrotransposon conflict. Cell Res. 2021 Jun 9.

Lanciano S, Cristofari G. Measuring and interpreting transposable element expression. Nat Rev Genet. 2020 Dec;21(12):721-736.

Repetitive DNA sequences account for almost half of the human and mouse genomes. Most of them are degenerated remnants of ancient mobile genetic elements. However, a subset of evolutionary recent transposable elements, particularly those belonging to the LINE-1 (L1) retrotransposon family, actively contribute to the plasticity of modern mammalian genomes and to the diversity of individual genomes. Their insertions into new genomic locations convey multiple cis-acting DNA regulatory elements, and can attract and even drive the evolution of chromatin factors and other host proteins. Because the vast majority of these potentially active L1s map outside of exons, predicting their impact on gene expression, transcript structure and function remains challenging. Considering the growing number of evidences that link L1 elements to the regulation of normal developmental processes but also to the etiology of diseases, understanding how L1s influence gene activity genome-wide represents a timely and relevant endeavor.

Here, we propose to test to which extent the youngest L1 retrotransposon families, L1-HS and L1-A, found in humans and mice, respectively, can influence gene expression at the genome-wide level. More specifically, the ImpacTE proposal will explore the impact of their 1) sequence, 2) transcription, and 3) chromatin states on gene regulation. This will be achieved at the global level rather than at individual loci, by combining recent technological developments, such as CRISPR-mediated (epi)genome engineering in cellula and in vivo, genetic screens and chromatin capture, ultra long-read sequencing, and retrotransposon mapping, while capitalizing on the expertise of the two scientific partners in the biology and bioinformatic analysis of transposons, mouse genetics and epigenetics. This proposal has the potential to reveal L1 insertions that alter gene expression in a cell-type- or tissue-specific manner and by which mechanisms they do so. Moreover, by relying on two mammalian representatives, mouse and human, and by including information from the cellular to the organismal level, we will gain complementary insights into the universal principles and specificities of the impact of L1s on mammalian genome regulation. Ultimately, our work will establish a rational basis for predicting the potential impact of thousands of retrotransposon copies identified in sequencing projects, as well as broaden our understanding of their role in the evolution of regulatory networks and novel protein functions in mammals.

Project coordination

Gael CRISTOFARI (Institut de Recherche sur le Cancer et le Vieillissement, Nice)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IC INSTITUT CURIE - SECT DE RECHERCHE
IRCAN Institut de Recherche sur le Cancer et le Vieillissement, Nice

Help of the ANR 433,365 euros
Beginning and duration of the scientific project: January 2020 - 42 Months

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