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Loss of Snhg5 disrupts cell-cycle regulation without altering cystogenesis in a mouse model of polycystic kidney disease.

ABSTRACT: Loss of Snhg5 disrupts cell-cycle regulation without altering cystogenesis in a mouse model of polycystic kidney disease.

PROVIDER: PRJNA1279975 | ENA |

REPOSITORIES: ENA

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Loss of Snhg5 disrupts cell-cycle regulation without altering cystogenesis in a mouse model of polycystic kidney disease.

Project description:Long non-coding RNAs (lncRNAs) regulate diverse cellular pathways and are increasingly linked to human disease. Snhg5 is frequently described as a pathogenic lncRNA in many human diseases, including cancer. Our previous studies revealed that Snhg5 is one of the most upregulated lncRNAs in multiple mouse models of polycystic kidney disease (PKD). Yet its role in renal biology and in autosomal dominant PKD (ADPKD) is not known. To elucidate the role of Snhg5, we generated a global Snhg5-null mouse. Homozygous animals were viable and displayed normal kidney morphology and function. RNA-sequencing of Snhg5-null kidneys and renal epithelial cells revealed common alterations in gene expression linked to cell cycle progression and DNA replication. At the molecular level, Snhg5-null cells showed an increased mitotic fraction, coinciding with depletion of ARPC5—a core ARP2/3 subunit— suggesting that reduced ARPC5 may contribute to this phenotype. To determine whether Snhg5 upregulation is pathogenic in mouse PKD, we crossed Snhg5-null mice with a collecting duct-specific Pkd1-mutant mouse model. Loss of Snhg5 did not attenuate cyst formation; if anything, disease severity was mildly but not significantly exacerbated. These findings indicate that Snhg5 modulates mitotic control and is dispensable for kidney development and cystogenesis in collecting duct-derived cysts.

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Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

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Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent, life-threatening monogenetic disorder that affects millions worldwide. Currently, therapeutic options are limited and often associated with complications. To find more effective treatments, this study aimed to understand the molecular mechanisms driving cystogenesis in ADPKD. By analysing various epigenetic factors, we identified a set of master transcription factors that guided a core regulatory circuitry and remodeled chromatin accessibility in ADPKD. We further explored the role of immune cells, notably macrophages, in the disease’s progression using single-cell RNA sequencing. A subgroup of Lhfpl2+/Fat3+ macrophages, which reactivated the Hgf-Met-Nfkb1-Runx1 pathways, was found essential for cystic cell fate transition. Targeting the identified epigenetic regulators, H3K4me3 and TF Runx1, effectively halted disease progression in a mouse model. These findings may lead to innovative treatments for ADPKD in humans.

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cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease

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Nrf2-mediated enhancer activation via phase separation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

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