Review
Chromatin dynamics underlying the precise regeneration of a vertebrate limb – Epigenetic regulation and cellular memory

https://doi.org/10.1016/j.semcdb.2019.04.006Get rights and content

Highlights

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    Amphibians and fish can regenerate an organ (limb, tail, or fin) after amputation.

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    The proper regulation of chromatin dynamics is required for organ regeneration.

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    The precise inheritance of cellular memory is essential for organ regeneration ability.

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    Epigenetic regulation may form the basis for cellular memory in organ regeneration.

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    The manipulation of chromatin dynamics may be critical to improve organ regeneration.

Abstract

Wound healing, tissue regeneration, and organ regrowth are all regeneration phenomena observed in vertebrates after an injury. However, the ability to regenerate differs greatly among species. Mammals can undergo wound healing and tissue regeneration, but cannot regenerate an organ; for example, they cannot regrow an amputated limb. In contrast, amphibians and fish have much higher capabilities for organ-level regeneration. In addition to medical studies and those in conventional mammalian models such as mice, studies in amphibians and fish have revealed essential factors for and mechanisms of regeneration, including the regrowth of a limb, tail, or fin. However, the molecular nature of the cellular memory needed to precisely generate a new appendage from an amputation site is not fully understood. Recent reports have indicated that organ regeneration is closely related to epigenetic regulation. For example, the methylation status of genomic DNA is related to the expression of regeneration-related genes, and histone-modification enzymes are required to control the chromatin dynamics for regeneration. A proposed mechanism of cellular memory involving an inheritable system of epigenetic modification led us to hypothesize that epigenetic regulation forms the basis for cellular memory in organ regeneration. Here we summarize the current understanding of the role of epigenetic regulation in organ regeneration and discuss the relationship between organ regeneration and epigenetic memory.

Section snippets

Introduction organ regeneration

Regeneration is a fundamental mechanism used to maintain multicellular organisms throughout their lifetime. Multicellular organisms are constantly at risk of accidental injury, so their ability to regenerate injured tissues or organs is important for their survival. Vertebrates vary in their regenerative ability [1], [2]. In amniotes including mammals, which have low regenerative abilities, physical trauma usually only results in wound healing. On the other hand, urodeles and fish have high

Requirement of epigenome regulation in organ regeneration

Several reports have indicated that epigenome regulators are required for organ regeneration [see Gilbert, [28], for review]. Among the histone modifications, H3K27ac is a marker of active enhancer elements (Fig. 1A). H3K4me3 is often located in the gene body, especially around TSSs and is associated with active gene expression (Fig. 1B). H3K27me3 is often located in silent enhancers and inactive gene bodies (Fig. 1C). In addition, DNA methylation is related to gene silencing. Numerous histone

Maintenance of cellular memory

Cellular memory in organ regeneration, including positional memory and lineage memory, may provide a clue for breaking the barrier between regenerative and non-regenerative animals. For example, although intercalary regeneration was discovered by artificial implant experiments and never happens in nature, it indicates that limb regeneration after an accidental injury uses positional information to determine the site from which the limb must be regenerated. Mice form a cartilaginous callus like

Attempts to ameliorate the regeneration potential through the epigenome

The development of epigenetic therapies, in which epigenome regulation is used to restore functional tissues/organs, is a subject of great interest. Several attempts to restore tissues/organs have been reported. For muscular dystrophy, in which excessive apoptosis/necrosis and regeneration result in muscle degeneration, pharmacological treatments have achieved partial rescue. TSA treatment restores muscle function in the mdx mouse, a muscular dystrophy model [103]. Three pharmacological drugs,

Funding sources

This work was supported by JSPS KAKENHI [grant number 17H06905] to SH; Kato Memorial Bioscience Foundation to SH; JSPS KAKENHI [grant number 16H04790] to HY; Hirosaki University Institutional Research Grant for Young investigators to HY; Grant for Basic Science Research Projects from The Sumitomo Foundation to HY; and the Takeda Science Foundation to HY.

Acknowledgment

We thank Dr. David Stocum for critical reading of the manuscript.

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