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  • Review Article
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Gene regulatory programmes of tissue regeneration

Nature Reviews Genetics volume 21, pages 511–525 (2020)Cite this article

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Abstract

Regeneration is the process by which organisms replace lost or damaged tissue, and regenerative capacity can vary greatly among species, tissues and life stages. Tissue regeneration shares certain hallmarks of embryonic development, in that lineage-specific factors can be repurposed upon injury to initiate morphogenesis; however, many differences exist between regeneration and embryogenesis. Recent studies of regenerating tissues in laboratory model organisms — such as acoel worms, frogs, fish and mice — have revealed that chromatin structure, dedicated enhancers and transcriptional networks are regulated in a context-specific manner to control key gene expression programmes. A deeper mechanistic understanding of the gene regulatory networks of regeneration pathways might ultimately enable their targeted reactivation as a means to treat human injuries and degenerative diseases. In this Review, we consider the regeneration of body parts across a range of tissues and species to explore common themes and potentially exploitable elements.

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Fig. 1: Comparison of tissue patterning events during ontogenetic and regenerative development.
Fig. 2: Relationship between genetic programmes of regeneration and embryogenesis.
Fig. 3: Discovering DNA regulatory elements involved in regeneration.
Fig. 4: Chromatin dynamics in regeneration.
Fig. 5: Phase transitions and injury-induced regeneration programmes.

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Acknowledgements

We thank N. Lee for contributions to the artwork in this Review. We thank A. Burghes, B. Blaser and C. Lepper for discussions, and J. Kang, V. Cigliola and M. Mokalled for comments on the manuscript. We apologize to colleagues in the field if the depth of the discussion of their work was limited as a result of space constraints. J.A.G. acknowledges funding from the American Heart Association (AHA) (17SDG33660922) and Ohio State University. K.D.P. acknowledges funding from the National Institutes of Health (R01HL136182, R01AR076342, R35HL150713), AHA and Fondation Leducq.

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Authors and Affiliations

  1. Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH, USA

    Joseph A. Goldman

  2. Regeneration Next, Duke University, Durham, NC, USA

    Kenneth D. Poss

  3. Department of Cell Biology, Duke University Medical Center, Durham, NC, USA

    Kenneth D. Poss

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  1. Joseph A. Goldman
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  2. Kenneth D. Poss
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The authors contributed equally to all aspects of the article.

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Glossary

Repatterning

The recapitulation of previous arrangements of cell types during regrowth.

Patterning

The developmental process by which cells acquire their identities, depending on their relative spatial positions within the embryo.

Ontogenetic

Relating to the developmental history of an organism from fertilization to adulthood.

Blastema

A mass of proliferative cells that forms at the salamander limb stump after amputation, ultimately giving rise to the new limb structures. Additional regeneration contexts in other species and tissues similarly invoke a blastema.

Dedifferentiate

Of a cell, to lose lineage-restricted characteristics, perhaps adopting a more developmentally primitive status.

Enhancer discovery

Classically, enhancers are validated using assays in which the test region is removed from its normal location and engineered into a heterologous context using reporters. Measures of endogenous enhancer activity have centred on scanning the accessibility of their chromatin, but CRISPR technology has made loss-of-function experiments feasible in virtually all lab model systems, enabling new definitions of enhancers based on function in vivo.

Sequencing depth

The number of high-throughput sequencing reads per given sample, indicative of the abundance of a transcript or chromatin feature.

Assay for transposase-accessible chromatin using sequencing

(ATAC-seq). In vitro assay for chromatin accessibility that measures the ability of a transposase to access the underlying DNA.

Pioneer factor

A transcription factor that directly binds nucleosomes and can therefore initiate gene regulation from a previously silenced state.

Reprogramming

The process of conversion from a committed cell type to a different cell type.

Karyokinesis

The division of nuclei after mitosis to compartmentalize the two daughter genomes.

Endoreplication

An incomplete form of mitosis in which the genome is replicated but the daughter cells never physically separate, leading to polyploidy.

Polyploid

A state in which cells have an increasing number of paired chromosomes beyond the normal 2N (for example, 4N, 8N, and so forth).

Immediate–early gene

(IEG). A gene that is activated rapidly because it does not require an intervening transcription event to produce already-poised activating factors.

Autotomy

Regulated removal of a body part as a defence mechanism — for example, a lizard losing its tail to escape a predator.

Jaw distraction

A surgical method for lengthening the jaw by cutting bone and resetting it more distally.

Karyolymph

The contents of the nucleus, including chromatin, nuclear fluid and particulate condensates such as the nucleolus.

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Goldman, J.A., Poss, K.D. Gene regulatory programmes of tissue regeneration. Nat Rev Genet 21, 511–525 (2020). https://doi.org/10.1038/s41576-020-0239-7

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