Glis3は常染色体優性多発性嚢胞腎疾患における嚢胞進行の修飾因子である

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations affecting polycystin-1 (PC1) or polycystin-2 (PC2). The existence of a 'cilia-dependent cyst activation' (CDCA) pathway has been identified by showing that structurally intact primary cilia are crucial for rapid cyst growth following loss of polycystins. We previously used translating ribosome affinity purification (TRAP) RNA-Seq on pre-cystic mouse kidneys to determine a translatome that meets the criteria for CDCA. From this, we identified Glis2 as an early effector of polycystin signaling and a potential target for therapy. Here, we investigate the role of Glis3 which, while not transcriptionally altered in ADPKD models, encodes a cilia-localized transcription factor belonging to the same gene family as Glis2.

We used live cell imaging along with gene and protein expression studies to determine the relationships between Glis3, Glis2 and PC1 expression. We used Glis3 conditional knockout mice to investigate the in vivo genetic interaction between Glis3 and Pkd1. We used gene expression and chromatin accessibility analyses by RNA-Seq and ATAC-Seq, respectively, on an allelic series of Glis3 and Pkd1 inactivation models to explore the genetic relationships between the two genes.

The ciliary localization of Glis3 was not affected by Pkd1 mutation status. Kidney selective inactivation of Glis3 by itself did not affect kidney structure or function, but dual inactivation of Glis3 and Pkd1 significantly worsened polycystic kidney disease. Integration of transcriptomic profiling and chromatin accessibility assays suggested that kidney tubule-specific Glis3 inactivation resulted in dysregulated fatty acid metabolism and alteration of circadian regulation.

Glis3 is a primary cilium localized transcription factor that genetically interacts with Pkd1 and modifies kidney epithelial cell metabolism and circadian function.