Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory
Lele Song1,2, Qinglan Li1,2, Lingbo Xia1,2,3
1Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Abstract:
How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL's histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.
Insights
Mutations in the epigenetic regulator ENL disrupt kidney development by altering cell differentiation, leading to Wilms tumor development in mice. A targeted inhibitor reversed these developmental defects, suggesting a potential therapeutic strategy.
Area of Science:
- Developmental biology
- Epigenetics
- Cancer biology
Background:
- The link between disrupted cell differentiation and tumorigenesis is not fully understood.
- Wilms tumor, a pediatric kidney cancer, is associated with epigenetic regulator mutations, but their role in kidney development is unclear.
Purpose of the Study:
- To investigate how a Wilms tumor-associated mutation in ENL (a histone acetylation reader) affects kidney development at a single-cell level.
- To explore the therapeutic potential of targeting mutant ENL.
Main Methods:
- Single-cell RNA sequencing and ATAC-sequencing in mouse models.
- Analysis of gene regulatory networks and chromatin accessibility.
- Pharmacological inhibition of mutant ENL.
Main Results:
- Mutant ENL promotes nephron progenitor commitment but restricts differentiation by dysregulating transcription factors like Hox clusters.
- Abnormal progenitors with lost kidney-specific chromatin identity were observed.
- Mutant ENL altered stromal progenitor transcriptomes, leading to Wnt signaling hyperactivation.
- These disruptions caused severe kidney developmental defects and mortality in mice.
Conclusions:
- Mutations in epigenetic regulators like ENL can profoundly disrupt kidney organogenesis by altering cell differentiation and gene regulation.
- Targeting mutant ENL's histone acetylation binding activity shows promise for reversing developmental defects and offers a potential therapeutic avenue for Wilms tumor.
