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Single-Cell multi-omics reveals disrupted gene regulatory landscape and cell differentiation by Wilms tumor-associated ENL mutation in the developing kidney (scRNA-Seq)

ABSTRACT: ENL is an epigenetic acetylation reader and represents the most frequently mutated epigenetic regulator in Wilms tumor. In this study, we established an in vivo mouse model with the ENL hotspot mutation Enl-T1. We performed single-cell RNA sequencing (scRNA-seq) analysis for the Enl-WT and T1 embryonic kidney to study the transcriptional mechanism underlying the kidney developing defeat induced by the Enl mutation.

ORGANISM(S): Mus musculus

PROVIDER: GSE243870 | GEO | 2024/05/27

REPOSITORIES: GEO

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Single-Cell multi-omics reveals disrupted gene regulatory landscape and cell differentiation by Wilms tumor-associated ENL mutation in the developing kidney (snATAC-Seq)

Project description:ENL is an epigenetic acetylation reader and represents the most frequently mutated epigenetic regulator in Wilms tumor. In this study, we established an in vivo mouse model with the ENL hotspot mutation Enl-T1. We performed single-nuclei ATAC sequencing (snATAC-seq) analysis for the Enl-WT and T1 embryonic kidney to study the open chromatin dynamics and gene regulatory mechanism underlying the kidney developing defeat induced by the Enl mutation.

2024-05-27 | GSE243868 | GEO

Single-Cell multi-omics reveals disrupted gene regulatory landscape and cell differentiation by Wilms tumor-associated ENL mutation in the developing kidney (ChIP-Seq)

Project description:ENL is an epigenetic acetylation reader and represents the most frequently mutated epigenetic regulator in Wilms tumor. In this study, we established an in vivo mouse model with the ENL hotspot mutation Enl-T1. Here we performed ChIP sequencing (ChIP-seq) analysis for human embryonuc kidney cell line HEK293 with ENL-WT or T1 to study the genomic binding site alterations induced by ENL mutation and whether those alterations can be rescued by treating the cells with the specific ENL inhibitor TDI-11055.

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Single-Cell multi-omics reveals disrupted gene regulatory landscape and cell differentiation by Wilms tumor-associated ENL mutation in the developing kidney (RNA-Seq)

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Project description:Gain-of-function mutations in the chromatin ‘reader’ ENL, identified in AML and Wilms tumor, have been shown to induce aberrant formation of transcriptional condensates in cellular systems. However, the precise role of these mutations and their condensate forming property in tumorigenesis remains unclear. By creating a conditional knock-in mouse model for the most prevalent ENL mutation, we establish ENL mutant as a bona fide oncogenic driver of acute myeloid leukemia in vivo. Heterozygous expression of ENL mutant perturbs the normal hematopoietic hierarchy and results in the aberrant expansion of myeloid progenitors with increased self-renewal property. Furthermore, the ENL mutant remodels histone modifications to alter differentiation processes and drive oncogenic gene expression during hematopoietic development. Importantly, targeted point mutagenesis to disrupt the condensate formation property completely abolishes ENL mutant’s oncogenic function in hematopoietic stem and progenitor cells (HSPCs). Lastly, short-term treatment with a small molecule inhibitor that blocks the acetyl-binding activity of ENL mutant reverts its impact on chromatin and significantly delays leukemia development in mice. Our studies reveal the crucial biological function of mutation-induced transcriptional condensates in chromatin regulation and cancer in vivo and provide proof-of-concept for targeting of pathogenic condensates as a promising therapy for certain cancers.

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Chromatin Analysis of Wilms Tumor Highlights Stem Cell Properties and a Renal Developmental Network

Project description:Wilms tumors are pediatric cancers thought to arise from kidney-specific stem cells. In order to identify transcriptional and epigenetic mechanisms that drive these malignant cells, we compared genomewide chromatin profiles of Wilms tumors to embryonic stem (ES) cells and normal kidney. Data represent examination of genome-wide chromatin modifications in primary Wilms tumors, fetal and mature kidney.

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Impaired Cell Fate by Gain-of-function Mutations in a Chromatin Reader

Project description:We previously identified the YEATS domain-containing protein ENL as a reader of histone acetylation. Recently, hotspot mutations in ENL were frequently found in Wilms’ tumor, the most common type of pediatric kidney cancer. Here, we report that these cancer-associated mutations in the ENL YEATS domain confer gain of functions in transcriptional control and impair kidney differentiation by driving self-reinforced chromatin targeting. Ectopic expression of ENL mutants in kidney cell lines resulted in transcriptional changes of genes enriched in embryonic nephron progenitors and Wilms’ tumor. When tested in a nephrogenesis assay, ENL mutant expression led to undifferentiated structures resembling those observed in human Wilms’ tumor. Genome-wide analyses revealed that while mutant ENL bound to largely similar genomic loci as wild-type ENL, they exhibited increased occupancy at a subset of targets, including developmentally critical genes such as the HOXA cluster. The cancer-associated mutations enabled self-reinforced recruitment of ENL on chromatin by promoting self-association, resulting in the formation of discrete nuclear puncta that are characteristic of phase-separated biomolecular condensates. Enhanced occupancy of ENL mutants led to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Collectively, our studies represent, to our knowledge, the first discovery that cancer-associated mutations in a chromatin reader drive self-reinforced chromatin targeting, which in turns, perturbs developmental programs and derails normal cell fate control during mammalian development towards an oncogenic path.

2020-01-03 | GSE125186 | GEO

Lin28 sustains early renal progenitors and induces Wilms tumor

Project description:Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that over-expression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in pathology highly reminiscent of Wilms tumor.

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