Rodriguez AM and Kang J (2020), Regeneration enhancers: Starting a journey to u...

XB-ART-56388

Semin Cell Dev Biol 2020 Jan 01; doi: 10.1016/j.semcdb.2019.04.003.

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Regeneration enhancers: Starting a journey to unravel regulatory events in tissue regeneration.

Rodriguez AM , Kang J .

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Regeneration, an ability to replace lost body parts, is widespread across animal species. While mammals poorly regenerate most tissues, teleost fish and urodele amphibians possess remarkable regenerative capacity. Earlier work demonstrated that genes driving regeneration are evolutionarily conserved, indicating that a key factor in diverse tissue regeneration is not the presence or absence of regeneration-driving genes but the mechanisms controlling activation of these genes after injury. Thus, understanding the regulatory events of tissue regeneration could provide the means for unlocking latent capacities for tissue regeneration. After injury, cells undergo extensive epigenetic changes to establish new transcriptional programs for tissue regeneration. Gene transcription in eukaryotes is a complicated process that requires specific interactions between trans-acting regulators and cis-regulatory DNA elements. Among cis-regulatory elements, enhancers are essential to control precise gene expression. Recently, multiple regeneration/injury-associated enhancers have been identified in several model organisms. In this review, we highlight recently discovered regeneration/injury enhancers and their specific characteristics. We also discuss how abnormal regulation of regeneration enhancers influences animal development and physiology. Investigation of regeneration enhancers potentially allows us to begin understanding the fundamental biology of tissue regeneration and inspires new solutions for manipulating regenerative ability.

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Genes referenced: aldh1a2 bmp5 eed egr2 gdnf klf5 mbp ncam1 runx2 shh sox10 sox9 wt1
GO keywords: tissue regeneration

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	Fig. 1. Diverse classes of regeneration/injury enhancers (A) Enhancers shared between development and regeneration/injury. The ZPA regulatory sequence (ZRS) and Raldh2 and Wt1 epicardial enhancers are activated by developmental and injury cues. (B) Regeneration/injury-restricted enhancers. Distinct enhancers are activated by development and regeneration. Bmp5 injury responsible elements, lepb-linked regeneration enhancer (LEN), Drosophila wnt-associated damage-induced enhancer (BRV118), and Samd14-Enh are responsible for regeneration or injury, but not development.
	Fig. 2. Dynamic activity of regeneration/injury-associated enhancers. (A) Regeneration/injury enhancer activity. Regeneration/injury enhancers are not active in uninjured tissues. Upon injuries, regeneration/injury enhancers are activated to drive target gene expression and their activity is maintained during regeneration. When regeneration or injury is resolved, the activity of regeneration/injury enhancers is returned to the level of the uninjured tissues. (B) Example of dynamic regeneration enhancer activity. Zebrafish LEN is not active in uninjured fin (0 day post-amputation (dpa)). Fin amputation activate LEN to direct reporter gene expression (12 h post-amputation (hpa)). LEN activity is maintained during regeneration (2 and 4 dpa). When fin regeneration completes (30 dpa), LEN activity is decommissioned and thus reporter gene expression is not detectable. (B) is adapted from [18].
	Fig. 3. Silenced regeneration/injury enhancer in uninjured tissues. After peripheral nerve injury, injury-induced enhancers emerge in Schwann cells. However, the loss of PRC2 activity results in aberrant activation of injury-induced enhancers in uninjured cells, leading to upregulation of myelin-regulated genes and subsequent hypermyelination and morphological change.
	Fig. 4. Tumor hijacks regeneration/injury enhancers for infinite division. Each track represents ATAC-seq peaks of epidermal stem cells (EpdSCs), hair follicle stem cells (HFSCs), wound-induced stem cells, and tumor stem cells of mouse skin. Under the homeostatic condition, epidermal stem cells (EpdSCs) and hair follicle stem cells (HFSCs) have their own open chromatin signatures. Upon wound injury, lineage-specific open chromatin signatures collapse and wound-specific signatures emerge. Wounded-induced and tumor stem cells exhibit similar global open chromatin profiles, but tumor stem cells display additional tumor-specific ATAC-seq peaks, indicating that misregulation of wound-induced regulatory events can lead to tumor.
	Fig. 5. Epigenetically memorized injury-induced enhancers. Each track represents ATAC-seq peaks of uninjured tissues (A), early (B) and late phase (C) of regenerating tissues, and completely regenerated tissues (D). A subset of injury-induced enhancers is not completely resolved long after completion of regeneration. These epigenetically memorized enhancers may mediate aberrant activation of immune cells in the central nervous system (CNS), resulting in chronic neuropathic pain. In mouse skin, the memorized enhancers contribute to faster healing of secondary wound.

References [+] :

Adam, Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. 2015, Pubmed