title: Modulation of tissue repair by regeneration enhancer elements.
abstract: How tissue regeneration programs are triggered by injury has received limited research attention. Here we investigate the existence of enhancer regulatory elements that are activated in regenerating tissue. Transcriptomic analyses reveal that leptin b (lepb) is highly induced in regenerating hearts and fins of zebrafish. Epigenetic profiling identified a short DNA sequence element upstream and distal to lepb that acquires open chromatin marks during regeneration and enables injury-dependent expression from minimal promoters. This element could activate expression in injured neonatal mouse tissues and was divisible into tissue-specific modules sufficient for expression in regenerating zebrafish fins or hearts. Simple enhancer-effector transgenes employing lepb-linked sequences upstream of pro- or anti-regenerative factors controlled the efficacy of regeneration in zebrafish. Our findings provide evidence for 'tissue regeneration enhancer elements' (TREEs) that trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Junsu
authors.initials: J
authors.lastname: Kang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Karra
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Dickson
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Tornini
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Nachtrab
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gemberling
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Goldman
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Poss
mesh_terms: D000107:Acetylation; D058500:Animal Fins / Q000293:injuries / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D006321:Heart; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D020738:Leptin / Q000096:biosynthesis / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology; D009928:Organ Specificity / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012038:Regeneration / Q000235:genetics* / Q000502:physiology*; D019076:Transgenes / Q000235:genetics; D014945:Wound Healing / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics* / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D006657:Histones; D020738:Leptin; D029961:Zebrafish Proteins; D008239:Lysine