Transposable elements, their controllers and the genesis of human-specific transcriptional networks

Project Information

TRANSPOS-X

Grant agreement ID: 694658

DOI

10.3030/694658

Project closed

EC signature date 13 December 2016

Start date 1 January 2017

End date 31 December 2021

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Switzerland

Periodic Reporting for period 4 - TRANSPOS-X (Transposable elements, their controllers and the genesis of human-specific transcriptional networks)

Reporting period: 2021-07-01 to 2021-12-31

Summary of the context and overall objectives of the project

This projects explores how the genome regulatory power of transposable elements (TEs), which contribute more than half of our DNA, and of their KRAB-containing zinc finger protein (KZFP) controllers shape human speciation, development and physiology, how alterations of this system can lead to pathologies, and how the resulting knowledge can be exploited in medicine, for instance to fight cancer.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our work has yielded an important sum of novel information on how some 350 human KZFPs recognize their TE targets, how these KZFPs functionally diversified throughout evolution, how they act during early embryogenesis to tame the regulatory power of TEs in order to facilitate its domestication for the benefit of the host, and how TEs and their KZFP controllers have fed higher vertebrates with cis- and trans-acting regulatory sequences that likely influence all aspects of human biology. Turning to the involvement of this system in human pathologies, we have discovered TE-based biomarkers of great potential value for precision oncology, and unveiled how the the genomic surveillance exerted by KZFPs is perverted in the context of cancer cells, where it confers protection against the genotoxic consequences of pro-oncogenic epigenetic changes. These results reveal an important role for a family of largely species-restricted proteins in the pathogenesis of human cancer, and also point to new avenues for therapeutic intervention.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our achievements shed an important light on what has so far been a black box of human biology, revealing intricate roles for TEs and their KZFP controllers in human speciation, development, physiology and disease susceptibility.

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