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Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape.
Song, Lele; Li, Qinglan; Xia, Lingbo; Sahay, Arushi Eesha; Qiu, Qi; Li, Yuanyuan; Li, Haitao; Sasaki, Kotaro; Susztak, Katalin; Wu, Hao; Wan, Liling.
Afiliação
  • Song L; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Li Q; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Xia L; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Sahay AE; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Qiu Q; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Li Y; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Li H; Department of the School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Sasaki K; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Susztak K; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Wu H; Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Wan L; Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun ; 15(1): 5937, 2024 Jul 15.
Article em En | MEDLINE | ID: mdl-39009564
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diferenciação Celular / Análise de Célula Única / Rim / Mutação Limite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diferenciação Celular / Análise de Célula Única / Rim / Mutação Limite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
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