期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：33
DOI：10.1073/pnas.2204338119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The kidney is an essential organ for filtrating metabolic waste products, and failure of this function leads to devastating disease. One possible cure is to regenerate functional tissue by reactivating intrinsic genetic programs for kidney formation. Here, we show that Krüppel-like factor 15 (Klf15) coregulates regeneration enhancers identified from the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and H3K27ac landscape. We also showed the adrenergic receptor gene is a downstream target of Klf15 and treatment with an agonist for this receptor stimulates nephric tubule regeneration and restores organ size. These results indicate the central role for Klf15-dependent adrenergic receptor signaling in the regeneration program and provide a new pharmacological target for regenerative therapy of kidney disease.
Despite the recent discovery of tissue regeneration enhancers in highly regenerative animals, upstream and downstream genetic programs connected by these enhancers still remain unclear. Here, we performed a genome-wide analysis of enhancers and associated genes in regenerating nephric tubules of
Xenopus laevis. Putative enhancers were identified using assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) analyses. Their target genes were predicted based on their proximity to enhancers on genomic DNA and consistency of their transcriptome profiles to ATAC-seq/ChIP-seq profiles of the enhancers. Motif enrichment analysis identified the central role of Krüppel-like factors (Klf) in the enhancer. Klf15, a member of the Klf family, directly binds enhancers and stimulates expression of regenerative genes, including
adrenoreceptor alpha 1A (
adra1a), whereas inhibition of Klf15 activity results in failure of nephric tubule regeneration. Moreover, pharmacological inhibition of Adra1a-signaling suppresses nephric tubule regeneration, while its activation promotes nephric tubule regeneration and restores organ size. These results indicate that Klf15-dependent adrenergic receptor signaling through regeneration enhancers plays a central role in the genetic network for kidney regeneration.
