Tissue Regeneration Enhancer Elements: A Way to Unlock Endogenous Healing Power

Abstract

Regenerative capacity is widespread throughout almost all animal phyla. However, the distribution pattern remains incompletely understood. Various examples show that very closely related species display different regenerative capacities. Why and how have diverse regenerative capacities evolved across species? One prevailing thought in the field of regeneration is that most regeneration‐associated factors are evolutionarily conserved, suggesting the existence of an innate tissue regeneration ability in all species. However, its regulation is differentially controlled in distinct species, resulting in heterogeneous regenerative capabilities. In this review, we discuss regeneration‐associated enhancers, the key cis‐regulatory elements controlling gene expression, their underlying molecular mechanisms, and their influence on regenerative capacity. Understanding the regulatory mechanisms of regeneration enhancers can provide fundamental insights into tissue regeneration and further help us develop therapeutic strategies to unlock latent healing powers in humans. Developmental Dynamics 248:34–42, 2019. © 2018 Wiley Periodicals, Inc.

Model systems for regeneration: zebrafish

“…The regenerative capacity in the zebrafish might rely on its capacity to activate specific gene regulatory networks in response to injury that are repressed in other animal models (Yang and Kang, 2018). Indeed, epigenetic modifications are necessary to trigger regeneration.…”

Genetically encoded thiol redox-sensors in the zebrafish model: lessons for embryonic development and regeneration

“…All regeneration requires proliferation of precursors and differentiation into the cell types of the destroyed tissue, with differences between tissues mainly in the origin of the precursors (stem cells or dedifferentiation) and the differentiation trajectories (re-or transdifferentiation). These processes frequently reemploy signaling molecules and networks active during embryonic development (Cardozo et al 2017;Sehring and Weidinger 2020;Yang and Kang 2019), either in the same organ (e.g. transcription factors involved in anterior-posterior patterning of limb buds (Nachtrab et al 2013)) or in another context (e.g.…”

“…simplet/ Fam35B, a regulator of Wnt signaling, newly expressed during larval and adult fin regeneration (Kizil et al 2009(Kizil et al , 2014). Interestingly, enhancer elements driving injury induced expression of leptin b in zebrafish can still be activated in mice, suggesting a conserved upstream regulatory network that in mammals has been uncoupled from regeneration-inducing processes, but could potentially be employed to stimulate regeneration (Kang et al 2016;Yang and Kang 2019).…”

Epigenetic treatment of dermatologic disorders

“…Skin epidermis, a self‐regenerating organ, constantly sheds and replaces damaged and worn‐out skin cells (Orioli & Dellambra, ; Yang & Kang, ; Zhang et al, ). Although mitochondrial dysfunction adversely affects primarily nonregenerative tissue, the neuromuscular system, and internal organs, cells in every tissue type, including skin, require a continuous and adequate supply of mitochondrial energy for their survival and proper function (Baeeri et al, ; Dinkova‐Kostova, Kostov, & Kazantsev, ; Joshi & Mochly‐Rosen, ; Martinelli et al, ; Naidoo, Hanna, & Birch‐Machin, ; Wlaschek, Singh, Sindrilaru, Crisan, & Scharffetter‐Kochanek, ; Zhou et al, ).…”