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Gain-of-function ENL YEATS domain mutations impede nephrogenesis through gene expression control [RNA-seq]

ABSTRACT: Hotspot gain-of-function mutations in the YEATS domain of the histone reader protein ENL have been identified in Wilms’ tumor. To investigate the pathogenic role of these cancer-associated ENL mutations in kidney development and tumorigenesis in vivo, we generated conditional knock-in mouse models mimicking patient-derived ENL YEATS mutations. Mice with heterozygous expression of ENLT mutants in either Six2+ nephrogenic or Foxd1+ stromal lineage exhibit severe yet distinct defects in kidney development, both resulting in neonatal lethality. The Six2-ENLT mutant kidney rudiments display compromised cap mesenchyme, scant proximal tubules and cystic glomeruli, indicative of premature commitment and differentiation blockade during nephrogenesis. Bulk and spatial transcriptomic analyses uncover aberrant activation of Hox genes and genes involved in cell fate commitment, especially the Wnt signaling pathway, in ENLT mutant-expressing nephrogenic cells. In contrast, the Foxd1-ENLT mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, accompanied with dysregulation of stromal genes involved in nephrogenesis and stroma-nephron crosstalk. Collectively, our study sheds lights on how ENL YEATS domain mutations impede nephrogenesis through different pathways in nephrogenic and stromal lineages, paving the way for further investigations into their roles in tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE266256 | GEO | 2025/02/20

REPOSITORIES: GEO

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Project description:Preterm neonates are at high risk for nephron loss under adverse clinical conditions (e.g., cardiocirculatory decompensation, nephrotoxic drugs). Importantly, the onset of renal damage potentially collides with the proceeding nephrogenesis of prematurity prior 36 weeks of gestation. Recent animal studies suggest that early nephron loss within this vulnerable phase is associated with more severe glomerular and tubulointerstitial alterations later in life, irrespective of the occurrence of arterial hypertension. It is known that nephrogenic pathways are reactivated after acute kidney injury supporting renal repair and regeneration. In this study we hypothesized that nephron loss during nephrogenesis leads to an alteration of the kidney developmental program which in turn impairs homeostasis and repair and thus aggravates kidney injury later in life. Preterm infants prior to 36 weeks of gestation show an active nephrogenesis after birth. In rats, nephrogenesis is still active until day 10 of life. Mimicking the human situation of acute nephron loss in preterm neonates with ongoing nephrogenesis, rats were uninephrectomized at day 1 of life (UNXd1). A second group of animals was uninephrectomized at day 14 of life (UNXd14), which resembles a nephron loss after terminated nephrogenesis. Age-matched control groups were sham operated. Three days after uninephrectomy the animals were sacrificed. Transcriptional renal changes were analyzed by RNAseqencing, followed by in silico functional pathway analysis. In UNXd1 animals 1182 genes were differentially regulated compared to the respective control group. The functional groups “renal development” and “kidney injury” were among the most differentially regulated groups and revealed distinctive alterations in UNXd1 animals. Reduced expression levels of candidate genes concerning renal development (Bmp7, Gdnf, Pdgf-B, Wt1) and kidney injury (nephrin, podocin, Tgf-β1) were detected in the kidney of UNXd1 animals. The downregulation of Bmp7 and Gdnf expression in the remaining kidney of UNXd1 animals persisted until day 28 of life. In UNXd14 rats Six2 was upregulated and Pax22 downregulated compared to controls. We conclude that neonatal nephron loss during active nephrogenesis affects renal development and induces persistently reduced expression levels of genes which in turn might hinder tissue repair after kidney injury later in life.

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Gain-of-function ENL YEATS domain mutations impede nephrogenesis through gene expression control [RNA-seq]

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