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Identification of GLIS2 direct target genes in kidney

ABSTRACT: Loss of function of the transcription factor GLIS2 in humans and mice causes nephronophthisis (NPHP). To obtain insights into the role of GLIS2 in the regulation of normal kidney functions and in the development of NPHP, we investigated GLIS2 direct target genes in kidney. Due to a lack of suitable GLIS2 antibody for chromatin immunoprecipitation (ChIP), we generated Glis2-HA mice in which HA tag was inserted before the TGA stop codon of GLIS2. Thereby, endogenous GLIS2 protein is expressed as a fusion protein with HA tag. GLIS2 ChIP-Seq was performed using HA antibody with kidneys from Glis2-HA mice. GLIS2 cistrome analysis identified many of genes associated with inflammation, ECM, and cell adhesion as direct targets by GLIS2.

ORGANISM(S): Mus musculus

PROVIDER: GSE282341 | GEO | 2026/04/02

REPOSITORIES: GEO

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Project description:Nephronophthisis (NPHP) is an autosomal recessive tubulointerstitial nephropathy classified as a renal ciliopathy disorder and recognised as the leading genetic cause of kidney failure in children and young adults. NPHP1 is the most common genetic cause and encodes nephrocystin-1, a protein that plays crucial roles in the primary cilium and cellular junctions. Here we utilise personalised medicine approaches and deep phenotyping, which enable us to explore mechanistic pathways and identify potential therapeutic strategies. In a family where we detected a homozygous NPHP1 whole-gene deletion in three affected siblings, we compared kidney biopsy tissue and human urine-derived renal epithelial cells (hURECs). Both the kidney biopsy and the hURECs demonstrated renal epithelial cells with an elongated and tortuous primary ciliary phenotype. Bulk RNA-seq on patient hURECs revealed disease signatures of the NPHP1 homozygous deletion, which included changes in EGFR signaling, as well as extracellular matrix interactions and adherens junctions, in line with the original description of nephrocystin-1 as an adapter protein at adherens junctions. Treatment of patient hURECs with alprostadil, a recently proposed therapy for NPHP, caused an increase in overall ciliation rate, but also an exaggerated primary ciliary length. In contrast, treatment of patient hURECs with an EGFR kinase inhibitor produced a phenotypic rescue of ciliary length and tortuosity. Following hUREC treatments, alprostadil did not fully restore the disease-associated transcriptional profile, whereas treatment with the EGFR kinase inhibitor AG556 caused a more complete rescue of the transcriptomic disease signature, in keeping with the observed phenotypic rescue. We conclude that patient-derived hURECS enable the deep phenotyping of nephronophthisis, replicate human kidney biopsy findings, and can be used to develop disease pathway signatures and screen candidate drug molecules, providing novel insights into disease pathogenesis and therapies. EGFR inhibition is now a potential therapy for renal ciliopathies, which should be tested within in vivo models of NPHP as a prelude to human studies.

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Identification of GLIS2 direct target genes in kidney

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