Transcriptional repatterning in early liver regeneration is driven by regeneration-specific and developmental enhancers

Tissue regeneration is characterised by a series of coordinated molecular and physiological events. Central to this process is the precise modulation of gene expression, triggered by changes in chromatin structure and temporal activation of distant regulatory elements. The mammalian liver is a unique organ with remarkable regenerative capabilities after injury or resection. Through the integration of chromatin accessibility and transcriptomic data following partial hepatectomy in mice, we show the highly dynamic nature of the early regenerative response at the chromatin level. Our findings suggest a model in which the expression of crucial regeneration genes is orchestrated by a plethora of cis-regulatory elements, each under the control of specific transcription factors. We have discovered enhancers exclusive to the regenerating tissue that collaborate with enhancers co-opted from various developmental stages. These, along with liver enhancers that exhibit increased activity post-injury, contribute to activating the transcriptional programs required for hepatocyte priming and proliferation. Altogether, these enhancers are likely under the control of the AP-1 complex together with other transcription factors such as ATF3 and NRF2. Furthermore, we show that a pivotal aspect of hepatic regeneration involves downregulation of genes associated with liver-specific functions in lipid metabolism through the inactivation of their enhancers, and we propose the potential role of regeneration-specific silencer elements governed by YY1.