Regeneration enhancers: a field in development

Abstract

The ability to regenerate tissues and organs following damage is not equally distributed across metazoans, and even highly related species can vary considerably in their regenerative capacity. Studies of animals with high regenerative potential have shown that factors expressed during normal development are often reactivated upon damage and required for successful regeneration. As such, regenerative potential may not be dictated by the presence or absence of the necessary genes, but whether such genes are appropriately activated following injury. The identification of damage-responsive enhancers that regulate regenerative gene expression in multiple species and tissues provides possible mechanistic insight into this phenomenon. Enhancers that are reused from developmental programs, and those that are potentially unique to regeneration, have been characterized individually and at a genome-wide scale. A better understanding of the regulatory events that, direct and in some cases limit, regenerative capacity is an important step in developing new methods to manipulate and augment regeneration, particularly in tissues that do not have this ability, including those of humans.

Keywords: enhancers; epigenetic; genetics; regeneration; regenerative capacity.

Graphical abstract

Figure 1.

Characterized regeneration enhancers (REs) and how they regulate gene expression in different tissue contexts of fish, flies, and mice. A: the lepb-linked enhancer (LEN) with separable tissue-specific modules that drive regenerative lepB expression in response to cardiac or appendage (fin) injury (13). B: the damage-responsive maturity-silenced enhancer of the WNT locus (DRMS^WNT, also BRV118) in, which activates wg and Wnt6 in response to damage in early third instar (L3) wing imaginal discs. Like the LEN, DRMS^WNT also has modular elements, but in this RE they regulate maturity-dependent activity in a single tissue rather than organ-specific behavior. The damage-responsive (DR) region mediates JNK-dependent expression of the flanking WNT genes, whereas the maturity-silencing region (MS) nucleates localized epigenetic silencing of the enhancer as the disc develops from early to late L3, coinciding with its loss of regenerative potential. Silencing is dependent on Polycomb group (PcG) proteins, manipulation of which can improve regenerative capacity (25). C: REs in the inner ear that regulate the transdetermination of support cells into auditory hair cells in response to their loss in early neonatal mice. Multiple REs associated with hair cell-specific genes, such as Atoh1, are silenced but primed in support cells through the addition of H3K27me3 and H3K4me1 marks (34). Within a week of maturation, the H3K4me1 marks are removed to decommission REs and curtail regenerative gene expression. [Image created with BioRender.com and published with permission.]