TRANSPOLOTL · Unraveling the role of transposable elements in the evolution of the gene-regulatory-networks driving limb regeneration in Axolotl
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-09-01 → 2024-08-31
- EU contribution
- €174,167
- Participants
- 2
- Scheme
- MSCA-IF
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Results in brief
Unraveling the role of transposable elements in the evolution of the gene-regulatory-networks driving limb regeneration in Axolotl
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.
Data: CORDIS, © European Union
Project objective
Salamanders are unique among tetrapods in that they possess the unrestricted capacity to fully regenerate limbs upon amputation. Why is this the only tetrapod taxon harbouring such a striking regenerative potential and how did it evolve are two of the biggest outstanding questions in regenerative research. Over the past two decades, transposable elements (TEs) have emerged as one of the major drivers of regulatory evolution, and it has yet to be explored whether their spectacular numbers in salamander genomes might provide a rationale for the emergence of such an extraordinary phenotype.The first aim of this work will be to develop an ensemble of state-of-the-art, long-read sequencing compatible approaches to profile the highly-repetitive Axolotl genome and identify the full complement of cis-regulatory-elements (CREs) driving limb regeneration. Two methyltransferase-based technologies for the profiling of chromatin accessibility and histone modifications will be developed, applied to the regenerating limb at different timepoints and later used to identify TE-derived CREs.This approach will not only shed light on the evolution and molecular mechanisms of limb regeneration but will also set the stage for the provocative possibility of using TEs to rewire mammalian gene-regulatory-networks (GRNs) and enable regeneration. While extensively employed in a wide range of genome engineering approaches, TEs have yet to be harnessed for the regulatory rewiring of GRNs in a directed evolution context. As part of the second aim of this work, I will establish an innovative, TE-based system for the regulatory rewiring of GRNs and employ it to screen for synthetic GRNs capable of reprogramming mouse fibroblasts into a limb-bud-like state, just as it occurs during regeneration in axolotl. Ultimately, by understanding the evolutionary mechanisms behind the emergence of limb regeneration, this work aims to provide an uncharted avenue for the development of regenerating mammals.
Original text from CORDIS.
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Data: CORDIS, © European Union