Cellular Regeneration Articulated with Chromatin Kinetics – CRACK

Context:
Regenerative healing allows reconstruction of an identical body part following wound or loss. Whereas mammals do have a limited ability to accomplish such processes naturally, this pales in comparison to spectacular cases of full body plan reconstruction following decapitation in planarians and cnidarians, or amputated limb regrowth in salamanders, as well as certain fish and insects. As a paradigmatic example, during leg regeneration, a transient pluripotent cell mass at the wound site, the blastema, forms, proliferates and differentiates to promote new limb formation. At the cellular level, this requires profound cell reprogramming events that must also be tightly controlled to prevent the emergence of cells with aberrant identities. These processes heavily rely on widespread changes in gene expression that must be precisely regulated by conserved and ubiquitous epigenomic effectors. Yet, despite their critical importance, how these players are coordinated at the chromatin level to enable regeneration and what differs in cells and organisms that are incompetent to regenerate is largely unknown.

Objectives and expected results:
Here, we will exploit the two-spotted cricket Gryllus bimaculatus as an established and tractable model for whole leg regeneration, to elucidate the underlying epigenomic mechanisms. First, we will map chromatin dynamics during regeneration, along the genome and in space by implementing innovative single molecule-resolution methodologies in epigenomics and microscopy. Second, we will compare natural and artificial situations where leg regeneration is perfect, flawed or absent to identify chromatin pathways involved in this plasticity and probe their function by genetic manipulations. Together, we expect our work to yield the most complete dynamic linear and 3D epigenome map of any regenerating tissue, and bring unprecedented understanding on how chromatin components facilitate or block limb regeneration.

Impact:
Regenerative medicine strives to reconstruct tissues and organs to mitigate injury and disease- or age-related degeneration. By understanding the bases of regeneration in crickets, we ultimately seek to detect the barriers that need to be lifted in human cells to facilitate targeted cell reprogramming and improve regenerative therapy.

Young investigator:
G.Orsi is an INSERM scientist, recently selected as a young group leader at the Institute for Advanced Biosicences (IAB) in Grenoble, with a solid publication track in the fields of epigenomics, super-resolution imaging and insect biology. Support from ANR will be critical to develop his original and promising research theme as an independent group leader.