Laurence Biggers | PubMed Health

PubMed2026

Disruption of a six-nucleotide miRNA motif improves PKD1 dosage and ameliorates polycystic kidney disease.

Disrupting microRNA interactions to restore protein expression from haploinsufficient genes offers a promising precision-therapy strategy for monogenic disorders. PKD1 heterozygosity underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder affecting nearly 12 million people worldwide, where reduced PKD1 dosage drives progressive cyst formation and kidney failure. We previously identified a 55-bp cis-repressive element in the PKD1 3'UTR. Here, we define a six-nucleotide miR-17 seed match within this element that is sufficient to reproduce PKD1 repression. In vivo base substitution of this motif stabilizes Pkd1 messenger RNA and increases polycystin-1 (PC1) protein levels, producing a robust reduction in cyst growth and preservation of kidney function in mouse models. To therapeutically recapitulate this effect, we developed a steric-blocking oligonucleotide that occludes the motif, stabilizes PKD1 transcript levels, increases PC1 expression, and mitigates cyst-pathogenic events in both murine and patient-derived ADPKD cells. Together, these findings establish a minimal, targetable cis-regulatory motif and provide proof of concept for oligonucleotide-mediated PKD1 derepression, while offering a potentially generalizable strategy to restore other haploinsufficient genes.

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PubMed2022

Enhancer and super-enhancer landscape in polycystic kidney disease.

Widespread aberrant gene expression is a pathological hallmark of polycystic kidney disease (PKD). Numerous pathogenic signaling cascades, including c-Myc, Fos, and Jun, are transactivated. However, the underlying epigenetic regulators are poorly defined. Here we show that H3K27ac, an acetylated modification of DNA packing protein histone H3 that marks active enhancers, is elevated in mouse and human samples of autosomal dominant PKD. Using comparative H3K27ac ChIP-Seq analysis, we mapped over 16000 active intronic and intergenic enhancer elements in Pkd1-mutant mouse kidneys. We found that the cystic kidney epigenetic landscape resembles that of a developing kidney, and over 90% of upregulated genes in Pkd1-mutant kidneys are co-housed with activated enhancers in the same topologically associated domains. Furthermore, we identified an evolutionarily conserved enhancer cluster downstream of the c-Myc gene and super-enhancers flanking both Jun and Fos loci in mouse and human models of autosomal dominant PKD. Deleting these regulatory elements reduced c-Myc, Jun, or Fos abundance and suppressed proliferation and 3D cyst growth of Pkd1-mutant cells. Finally, inhibiting glycolysis and glutaminolysis or activating Ppara in Pkd1-mutant cells lowerd global H3K27ac levels and its abundance on c-Myc enhancers. Thus, our work suggests that epigenetic rewiring mediates the transcriptomic dysregulation in PKD, and the regulatory elements can be targeted to slow cyst growth.

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