DS0405 -

Revealing the uniqueness of repetitive DNA: epigenetic regulation of L1 retrotransposons in human somatic cells at unprecedented resolution – RETROMET

Submission summary

Repetitive DNA accounts for half of our genome. Most of these repeats are retrotransposons, i.e. mobile genetic elements, which proliferate through an RNA-mediated copy-and-paste mechanism, called retrotransposition. Only one family of retrotransposons is able to autonomously generate new copies in modern humans: the L1 elements, and more specifically, those of the L1HS subfamily. Their mobility results in germline and somatic insertion polymorphisms, driving genome plasticity in health and disease. Epigenetic mechanisms, such as DNA methylation and repressive chromatin complexes, play a central role to limit their activity. However, due to the high levels of similarity between copies, and of insertion polymorphisms between individuals, it is currently not established if all L1HS loci are similarly regulated. The aim of this proposal is to uncover the epigenetic pathways controlling L1HS expression at single copy resolution and to determine how some of them can escape silencing. To this end, we have comprehensively mapped L1HS elements in 12 normal or transformed human cell lines well characterized by the ENCODE project (e.g. RNA-seq and ChIP-seq) and we integrated these data to identify actively transcribed and repressed L1HS copies. This provides us with cellular systems amenable to experimentations in which the genomic location and transcriptional state of each individual L1HS copy are precisely defined. We will now take advantage of this unique resource to uncover the epigenetic pathways controlling the transcriptional reactivation and silencing of individual L1HS copies in human somatic cells. More specifically, this will be achieved by:
(i) Obtaining the DNA methylation and hydroxymethylation status of all individual L1HS copies in 12 human cell lines.
(ii) Exploring the causal link between L1HS demethylation or hydroxymethylation and their reexpression.
(iii) Uncovering the mechanisms and pathways of epigenetic L1HS repression through genetic screens.
This proposal, by studying retrotransposon silencing in somatic cells at the level of individual copies, will improve our global understanding of the mechanisms that maintain the integrity of our genome, as well as the genetic or epigenetic basis of somatic genome remodeling, a process potentially involved in normal or pathological aging.

Project coordination

Gael CRISTOFARI (Institute for Research on Cancer and Aging of 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

IRCAN Institute for Research on Cancer and Aging of Nice
UMR 7216 Epigenetics and Cell Fate

Help of the ANR 480,684 euros
Beginning and duration of the scientific project: October 2016 - 48 Months

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