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TREEs – Tissue Regeneration Branches-out into Mammals?



Review of “Modulation of tissue repair by regeneration enhancer elements” from Nature by Stuart P. Atkinson

It’s not often that we look with envy at fish and lizards, but their ability to regenerate tissues with apparent ease [1, 2] surely garners a certain amount of jealous glances. The next best thing we can do is to understand the molecular/genetic underpinnings of this process in the hope that we can make mammalian regeneration a clinical reality.

Enhancer regions mediate the stage and tissue-specific regulation of gene expression during development and it was to these regions that researchers from the laboratory of Kenneth D. Poss (Duke University Medical Center, North Carolina, USA) looked towards to better understand how some vertebrates activate the genetic programs required for tissue regeneration following injury. Their new study in zebrafish now describes the discovery of ‘tissue regeneration enhancer elements’ (TREEs) and their potential for the enhancement of mammalian regeneration [3].

Using injured and matched non-injured adult zebrafish tissue, the authors first set out to identify genes associated with tissue regeneration. This identified 69 highly induced genes, with the leptin b (lepb) energy homeostasis gene [4] at the top of the list. Analysis of the regulatory regions of the lepb gene after injury then identified a short sequence surrounding an activated distal enhancer which had the ability to drive regeneration-activated gene expression from multiple promoter sequences. Further dissection of this TREE sequence, named the lepb-linked enhancer (LEN), generated more surprises; differing regions of the LEN seemed to control tissue regeneration in the tail tip as compared to the heart, suggesting tissue-specificity.

Excitingly, the LEN sequence could be utilized to preferentially deliver supporting factors to damaged areas to induce repair. The authors created transgenic zebrafish carrying tissue-specific LEN-lepb promoter constructs controlling the expression of genes involved in the regeneration of the zebrafish fin (fgf20a) and heart (nrg1). After injury, the observed increase in expression of both fgf20a and nrg1 mediated an improved rate of repair by aiding the normal reparative responses.

But has this TREE sequence “branched-out” into mammalian genomes? Unfortunately, analysis in humans and mice demonstrated little primary sequence conservation of the LEN sequence. However, the creation of mouse lines bearing a construct containing a murine hsp68 promoter and a lacZ reporter gene under the control of the LEN established that the LEN could interact with the mammalian transcriptional machinery to direct injury-induced expression. 

Not only does this study provide evidence for the existence of TREEs, it also provides evidence that the integration of such elements into mammalian systems may lead to enhanced tissue regeneration following injury. The authors of the study also point to another study in mice which may also have identified a mammalian TREE [5], suggesting that a method to quickly and safely express pro-regenerative genes in a tissue- and injury- specific manner may be at hand. 


  1. Poss KD Advances in understanding tissue regenerative capacity and mechanisms in animals. Nat Rev Genet 2010;11:710-722.
  2. Nacu E and Tanaka EM Limb regeneration: a new development? Annu Rev Cell Dev Biol 2011;27:409-440.
  3. Kang J, Hu J, Karra R, et al. Modulation of tissue repair by regeneration enhancer elements. Nature 2016;532:201-206.
  4. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432.
  5. Guenther CA, Wang Z, Li E, et al. A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury. Bone 2015;77:31-41.