Epigenetic Regulation of Organ Regeneration in Zebrafish

Abstract

The zebrafish is broadly used for investigating de novo organ regeneration, because of its strong regenerative potential. Over the past two decades of intense study, significant advances have been made in identifying both the regenerative cell sources and molecular signaling pathways in a variety of organs in adult zebrafish. Epigenetic regulation has gradually moved into the center-stage of this research area, aided by comprehensive work demonstrating that DNA methylation, histone modifications, chromatin remodeling complexes, and microRNAs are essential for organ regeneration. Here, we present a brief review of how these epigenetic components are induced upon injury, and how they are involved in sophisticated organ regeneration. In addition, we highlight several prospective research directions and their potential implications for regenerative medicine.

Keywords: DNA methylation; SWI/SNF complex; histone modification; miRNA; regeneration; zebrafish.

Figure 1

Schematic illustration of epigenetic regulation. Epigenetic regulation mainly comprises DNA methylation, histone modifications, chromatin remodeling complexes, and non-coding RNAs. CHD—CHD chromatin-remodeling complexes; K4, 9, 20, 27, 36, and R3—histone lysine (K) or arginine (R) methylation; K5, 8, 14, 18, and 23—histone lysine (K) acetylation; INO80—INO80 chromatin-remodeling complexes; ISWI—SWI-like ATP-dependent chromatin-remodeling complexes; miRNA—microRNA; Me—DNA methylation; pri-miRNA—primary miRNA; pre-miRNA—precursor miRNA; S10 and 28—histone phosphorylation; SWI/SNF—SWItch/sucrose nonfermentable complex; TF—transcription factor.

Figure 2

Composition of the mammalian SWI/SNF complex and Brg1 function in zebrafish heart regeneration. (A) Subunit composition of the mammalian SWI/SNF complex; (B) Cartoon showing how Brg1 regulates zebrafish cardiomyocyte proliferation and regeneration via a derepression mechanism. The injury-induced Brg1, via its interaction with Dnmt3ab, inhibits the expression of cdkn1c by increasing the methylation level of CpG sites at the cdkn1c promoter [61].