Enhancer selection dictates gene expression responses in remote organs during tissue regeneration

Fei Sun, Jianhong Ou, Adam R. Shoffner, Yu Luan, Hongbo Yang, Lingyun Song, Alexias Safi, Jingli Cao, Feng Yue, Gregory E. Crawford, Kenneth D. Poss*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Acute trauma stimulates local repair mechanisms but can also impact structures distant from the injury, for example through the activity of circulating factors. To study the responses of remote tissues during tissue regeneration, we profiled transcriptomes of zebrafish brains after experimental cardiac damage. We found that the transcription factor gene cebpd was upregulated remotely in brain ependymal cells as well as kidney tubular cells, in addition to its local induction in epicardial cells. cebpd mutations altered both local and distant cardiac injury responses, altering the cycling of epicardial cells as well as exchange between distant fluid compartments. Genome-wide profiling and transgenesis identified a hormone-responsive enhancer near cebpd that exists in a permissive state, enabling rapid gene expression in heart, brain and kidney after cardiac injury. Deletion of this sequence selectively abolished cebpd induction in remote tissues and disrupted fluid regulation after injury, without affecting its local cardiac expression response. Our findings suggest a model to broaden gene function during regeneration in which enhancer regulatory elements define short- and long-range expression responses to injury.

Original languageEnglish (US)
Pages (from-to)685-696
Number of pages12
JournalNature Cell Biology
Volume24
Issue number5
DOIs
StatePublished - May 2022

Funding

We thank Duke Zebrafish Core for animal care, Duke Center for Genomic and Computational Biology for advice, A. Dickson and K. Oonk for assistance with ISH, J. Kang, Y. Diao, J. A. Goldman, M. Pronobis, V. Cigliola, R. Yan, K. Ando, L. Slota-Burtt and R. Karra for comments on the manuscript and Y. Diao, J. Rawls, B. Black and N. Bursac for discussions. We acknowledge research support from NIH (R01 HL155607 to J.C.; R35 GM 124820 to F.Y.; R35 HL150713 and R01 HL136182 to K.D.P.) and from AHA and Fondation Leducq to K.D.P.

ASJC Scopus subject areas

  • Cell Biology

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