Duke Regeneration Center, Duke University, Durham, NC, USA.
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Nat Cell Biol. 2022 May;24(5):685-696. doi: 10.1038/s41556-022-00906-y. Epub 2022 May 5.
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.
急性创伤会刺激局部修复机制，但也会对远离损伤部位的结构产生影响，例如通过循环因子的活性。为了研究组织再生过程中远程组织的反应，我们对实验性心脏损伤后的斑马鱼大脑进行了转录组分析。我们发现，转录因子基因 cebpd 在脑室管膜细胞和肾管状细胞中被远程上调，除了在心脏外膜细胞中的局部诱导。cebpd 突变改变了局部和远程心脏损伤反应，改变了心脏外膜细胞的循环以及远程液体积分之间的交换。全基因组分析和转基因确定了 cebpd 附近的一个激素反应增强子，该增强子处于允许状态，使心脏、大脑和肾脏在心脏损伤后能够快速表达基因。删除该序列选择性地消除了远程组织中 cebpd 的诱导，并破坏了损伤后的液体调节，而不影响其局部心脏表达反应。我们的发现提出了一个模型，即在再生过程中扩大基因功能，其中增强子调控元件定义了对损伤的短期和长期表达反应。
