Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape

Lele Song, Qinglan Li, Lingbo Xia, Arushi Eesha Sahay, Qi Qiu, Yuanyuan Li, Haitao Li, Kotaro Sasaki, Katalin Susztak, Hao Wu and Liling Wan ()
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Lele Song: University of Pennsylvania
Qinglan Li: University of Pennsylvania
Lingbo Xia: University of Pennsylvania
Arushi Eesha Sahay: University of Pennsylvania
Qi Qiu: University of Pennsylvania
Yuanyuan Li: Tsinghua University
Haitao Li: Tsinghua University
Kotaro Sasaki: School of Veterinary Medicine
Katalin Susztak: University of Pennsylvania
Hao Wu: University of Pennsylvania
Liling Wan: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-26

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50171-w

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