RESUMO
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
Diferenciação Celular , Rim , Mutação , Análise de Célula Única , Animais , Camundongos , Rim/metabolismo , Rim/patologia , Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Cromatina/metabolismo , Epigênese Genética , Tumor de Wilms/genética , Tumor de Wilms/patologia , Tumor de Wilms/metabolismo , Histonas/metabolismo , Acetilação , Humanos , Organogênese/genética , Via de Sinalização Wnt/genética , Néfrons/metabolismo , Néfrons/patologia , Néfrons/embriologia , Transcriptoma/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Feminino , Masculino , MultiômicaRESUMO
The association between ear and kidney anomalies has long been recognized. However, little is known about the underlying mechanisms. In the last two decades, embryonic development of the inner ear and kidney has been studied extensively. Here, we describe the developmental pathways shared between both organs with particular emphasis on the genes that regulate signalling cross talk and the specification of progenitor cells and specialised cell types. We relate this to the clinical features of oto-renal syndromes and explore links to developmental mechanisms.
Assuntos
Síndrome Brânquio-Otorrenal , Nefropatias , Humanos , Síndrome Brânquio-Otorrenal/genética , Rim , Organogênese/genética , Desenvolvimento EmbrionárioRESUMO
In vitro regeneration of shoots from leaf explants of the Paradise tree (Melia azedarach L.) was studied. Three different portions (proximal portion, distal portion and rachis of the leaflets) of three developmental stages (folded, young still expanding and completely expanded) of leaves of 10-15 year old plants of seven genotypes were cultured on Murashige and Skoog (1962) medium (MS) supplemented with 1 mg x l(-1) benzylaminopurine (BAP) + 0.1 mg x l(-1) kinetin (KIN) + 3 mg x l(-1) adenine sulphate (ADS). The rachis of the leaflets of the completely expanded leaves was found to be the most responsive tissue, in most of the genotypes employed. Shoot regeneration occurred in leaf explants of all the genotypes tested. The best genotype for shoot regeneration was clone 4. Rooting was induced on MS medium supplemented with 2.5 mg x l(-1) 3-indolebutyric acid, IBA, (4 days) followed by subculture on MS lacking growth regulators (26 days). Complete plants were transferred to soil.