Unraveling the role of transposable elements in the evolution of the gene-regulatory-networks driving limb regeneration in Axolotl

Project Information

TRANSPOLOTL

Grant agreement ID: 101033244

DOI

10.3030/101033244

Project closed

EC signature date 6 April 2021

Start date 1 September 2022

End date 31 August 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 174 167,04

EU contribution

€ 174 167,04

Coordinated by

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Austria

Periodic Reporting for period 1 - TRANSPOLOTL (Unraveling the role of transposable elements in the evolution of the gene-regulatory-networks driving limb regeneration in Axolotl)

Reporting period: 2022-09-01 to 2024-08-31

Summary of the context and overall objectives of the project

The project addresses the extraordinary regenerative ability of salamanders, particularly the axolotl, which can regrow limbs, heart tissue, and even parts of the spinal cord, a capability not found in mammals. This research aims to uncover the molecular mechanisms behind this regeneration, focusing on identifying gene-regulatory elements that enable such complex tissue regrowth. Understanding these mechanisms has significant implications for human regenerative medicine, as insights could guide the development of therapies to enhance tissue repair in humans.

The project’s main objectives are to (1) map the regulatory landscape of the axolotl genome during limb regeneration and identify the role of transposable elements (TEs) in gene regulation, and (2) test if introducing similar gene-regulatory networks into mouse cells could trigger regenerative-like states. These goals are pursued by developing advanced sequencing methods to profile gene activity within the large, repetitive axolotl genome and using genetic editing tools to explore the function of specific regulatory elements in limb regeneration.

In summary, the project seeks to bridge a fundamental gap in understanding how certain animals regenerate complex tissues and explore whether these molecular strategies can be applied to other species, opening new possibilities for regenerative medicine.

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

Since the start of the project, substantial progress has been made toward uncovering the gene-regulatory mechanisms that drive limb regeneration in axolotls. Key achievements include the successful development and optimization of advanced sequencing methods compatible with the highly repetitive axolotl genome, which has lead to a new genome assembly. Furthermore these methods enabled the detailed mapping of transposable elements (TEs) within the genome, identifying numerous regulatory elements that appear to contribute specifically to regeneration. This work has explored how certain TEs may play an integral role in gene expression changes that support tissue regrowth. We are currently investigating whether these regulatory elements are found in the human genome, as well as when did they arise in evolution.

For dissemination, the findings have been shared through one open-access publication, ensuring that insights are available to the scientific community. Presentations at five international conferences have raised awareness of the potential regenerative applications of this research, while further planned publications and associated dissemination activities aim to reach a broader audience. In summary, the project has not only advanced our understanding of regeneration at a genomic level but has also introduced novel tools and techniques valuable for ongoing regenerative research in the axolotl.

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)

The project has advanced beyond the current state of regenerative biology by successfully developing new methods to map complex, repetitive genomic elements in the axolotl. By pinpointing specific transposable elements (TEs) that may drive gene-regulatory networks essential to limb regeneration, this research has opened up fresh perspectives on how genetic elements contribute to complex tissue regeneration—a capability unique to certain species like salamanders.

Expected results by the project’s end include a comprehensive map of regulatory elements active during axolotl regeneration and new tools for studying gene regulation in highly repetitive genomes.

By shedding light on the evolutionary mechanisms leading to axolotls impressive ability to regenerate nearly any organ, this project paves the way towards understanding what are the molecular interventions that would enable humans to regenerate lost appendages like arms and legs. This is an important societal challenge that affects millions of people throughout the world who have sustained major injuries through accidents, war, and disease.

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