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

Area of Science:

• Developmental Biology
• Regenerative Medicine
• Genomics

Background:

• Acute trauma initiates local tissue repair but can also induce systemic responses.
• Understanding remote tissue reactions during regeneration is crucial for comprehensive injury management.
• Circulating factors play a role in mediating distant tissue responses to injury.

Purpose of the Study:

• To investigate remote tissue responses during tissue regeneration.
• To profile transcriptomes of zebrafish brains following experimental cardiac damage.
• To identify genes and regulatory elements involved in both local and distant injury responses.

Main Methods:

• Transcriptome profiling of zebrafish brains after experimental cardiac damage.
• Analysis of transcription factor gene cebpd expression in various tissues (heart, brain, kidney).
• Genome-wide profiling and transgenesis to identify and manipulate regulatory elements.
• Investigating the effects of cebpd mutations and enhancer deletion on injury response and fluid regulation.

Main Results:

• The transcription factor gene cebpd was upregulated remotely in brain ependymal and kidney tubular cells, in addition to local induction in epicardial cells after cardiac damage.
• cebpd mutations affected both local cardiac repair and distant tissue responses, including cell cycling and fluid compartment exchange.
• A hormone-responsive enhancer near cebpd was identified, enabling rapid gene expression in multiple organs post-injury.
• Deletion of this enhancer selectively abolished remote cebpd induction and disrupted fluid regulation without impacting local cardiac response.

Conclusions:

• A novel model for gene function during regeneration is proposed, where enhancer elements dictate short- and long-range injury responses.
• Specific enhancer elements can mediate rapid, long-range gene expression changes in response to tissue injury.
• This study highlights the intricate systemic communication during tissue regeneration and identifies key regulatory mechanisms.