Suzuki N and Ochi H (2020), Regeneration enhancers: A clue to reactivation ...

XB-ART-56719

Dev Growth Differ 2020 Jun 01;625:343-354. doi: 10.1111/dgd.12654.

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Regeneration enhancers: A clue to reactivation of developmental genes.

Suzuki N , Ochi H .

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During tissue and organ regeneration, cells initially detect damage and then alter nuclear transcription in favor of tissue/organ reconstruction. Until recently, studies of tissue regeneration have focused on the identification of relevant genes. These studies show that many developmental genes are reused during regeneration. Concurrently, comparative genomics studies have shown that the total number of genes does not vastly differ among vertebrate taxa. Moreover, functional analyses of developmental genes using various knockout/knockdown techniques demonstrated that the functions of these genes are conserved among vertebrates. Despite these data, the ability to regenerate damaged body parts varies widely between animals. Thus, it is important to determine how regenerative transcriptional programs are triggered and why animals with low regenerative potential fail to express developmental genes after injury. Recently, we discovered relevant enhancers and named them regeneration signal-response enhancers (RSREs) after identifying their activation mechanisms in a Xenopus laevis transgenic system. In this review, we summarize recent studies of injury/regeneration-associated enhancers and then discuss their mechanisms of activation.

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Species referenced: Xenopus laevis
Genes referenced: arid3a crebbp lhx1 pax2 wnt6
GO keywords: regeneration

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	Figure 1. (a) Extraction of candidate enhancers using evolutionarily conserved noncoding sequences; plot using the comparative genomics alignment tool VISTA; comparison of human (Homo sapiens), mouse (Mus musculus), and frog (Xenopus tropicalis) Pax2 loci; the pink peak indicates the conserved noncoding sequences and the blue peak indicates exons. (b) Extraction of candidate enhancers based on epigenetic profiling of H3K4me1, H3K4me3, and H3K27ac, and the binding of histone acetyltransferase p300; H3K4me1, H3K27ac, and p300 are often associated with enhancers, whereas H3K4me3 and H3K27ac are often present at active promoters. The image was adapted and modified from Prescott et al. (2015)
	Figure 2. (a) Regenerative mechanisms of the damage response enhancer for Drosophila wing imaginal discs; Wg and Wnt6 expression are upregulated in response to damage via the damage response enhancer in unmatured discs. In contrast, immediately adjacent regulatory elements promote methylation of H3K27me3 across the Wnt gene cluster. This methylation event prevents regeneration of wing imaginal discs. The image was adapted and modified from Harris et al., (2016). (b) Genomic DNA regions surrounding the lepb gene and profiles of H3K27ac in uninjured and regenerating hearts; transgenic analyses showed that H3K27ac‐rich elements have enhancer activity in regenerating zebrafish hearts
	Figure 3. (a) Extraction of candidate enhancers for Lhx1 using evolutionarily conserved noncoding sequences; the magenta box indicates the noncoding evolutionarily conserved sequence (CNS) between frogs and fish. The blue box indicates the CNS among vertebrates. (b) Identification of regeneration‐related enhancers for frog nephric tubules; nonmosaic founder frogs are generated by injecting reporter DNA and sperm nuclei into unfertilized eggs. Functional enhancers in regenerating tissues can be identified using founder transgenic animals. (c) Mechanisms of activation of regeneration signal‐response enhancers (RSREs); with the H3K9me3 demethylase–Kdm4 complex, Arid3a binds to RSREs and reduces H3K9me3 levels, thereby promoting the expression of Lhx1 during regeneration of nephric tubules
	Figure 4. Injury/regeneration‐specific enhancers and developmental enhancers; genes that initiate the developmental cascade may have injury/regeneration‐specific enhancers. In contrast, genes located downstream of the cascade may reuse developmental enhancers for regeneration

References [+] :

Anderson, Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration. 2009, Pubmed