Journal
DEVELOPMENT
Volume 147, Issue 24, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.194019
Keywords
Enhancer; Gene expression; Heart; Injury; Regeneration; Zebrafish
Categories
Funding
- National Institutes of Health, under a Ruth L. Kirschstein National Research Service Award from the National Heart, Lung and Blood Institute [T32 HL 007936]
- National Institute Of General Medical Sciences [T32 GM 007133]
- U.S. Department of Agriculture Hatch grant
- University of Wisconsin-Madison UW2020 Round 6 award
- National Institutes of Health [R35 GM 137878]
- American Heart Association [AHA16SDG30020001]
- University of Wisconsin Carbone Cancer Center Support Grant [P30 CA014520]
- University of Wisconsin-Madison start-up funds [AAC8355, AAC8979, AAC6429, AAG9756]
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Heart regeneration in regeneration-competent organisms can be accomplished through the remodeling of gene expression in response to cardiac injury. This dynamic transcriptional response relies on the activities of tissue regeneration enhancer elements (TREEs); however, the mechanisms underlying TREEs are poorly understood. We dissected a cardiac regeneration enhancer in zebrafish to elucidate the mechanisms governing spatiotemporal gene expression during heart regeneration. Cardiac lepb regeneration enhancer (cLEN) exhibits dynamic, regeneration-dependent activity in the heart. We found that multiple injury-activated regulatory elements are distributed throughout the enhancer region. This analysis also revealed that cardiac regeneration enhancers are not only activated by injury, but surprisingly, they are also actively repressed in the absence of injury. Our data identified a short (22 bp) DNA element containing a key repressive element. Comparative analysis across Danio species indicated that the repressive element is conserved in closely related species. The repression mechanism is not operational during embryogenesis and emerges when the heart begins to mature. Incorporating both activation and repression components into the mechanism of tissue regeneration constitutes a new paradigm that might be extrapolated to other regeneration scenarios.
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