Glis3 Is a Modifier of Cyst Progression in Autosomal Dominant Polycystic Kidney Disease.

KEY POINTS: Dual inactivation of Glis3 and Pkd1 exacerbated polycystic kidney disease compared with Pkd1 inactivation alone in mouse models of autosomal dominant polycystic kidney disease. RNA-Seq and ATAC-Seq suggested Glis3 inactivation resulted in dysregulated fatty acid metabolism and alteration of circadian regulation. Glis3 was involved in a transcriptional network consisting of the transcription factors HNF1 homeobox B, hepatic nuclear factor 4, alpha, and D site albumin promoter binding protein.

BACKGROUND

Autosomal dominant polycystic kidney disease is caused by mutations affecting polycystin-1 or polycystin-2. The existence of a cilia-dependent cyst activation 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 RNA-Seq on precystic mouse kidneys to determine a translatome that meets the criteria for cilia-dependent cyst activation. 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 autosomal dominant polycystic kidney disease models, encodes a cilia-localized transcription factor belonging to the same gene family as Glis2 .

METHODS

We used live cell imaging along with gene and protein expression studies to determine the relationships between Glis3, Glis2, and polycystin-1 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.

RESULTS

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.

CONCLUSIONS

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