Impaired Cell Fate by Gain-of-function Mutations in a Chromatin Reader
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA515491 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8448080.fastq.gz | Fastqsanger.gz | |||
| SRR8448090.fastq.gz | Fastqsanger.gz | |||
| SRR8448100.fastq.gz | Fastqsanger.gz | |||
| SRR8448110_1.fastq.gz | Fastqsanger.gz | |||
| SRR8448110_2.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.
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Project description:Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5AΔExon27) and the encoding of a protein with a novel 39-amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C-terminus of mutant KIF5A results in a constitutively active state. Further, mutant KIF5A possesses novel protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.
2022-06-09 | PXD031012 | Pride
Project description:We used human or mouse MLL2-impaired cells (including a human DSET MLL2 cell line,) as well as their parental controls, and measured mutations in histones and a few other genes that were affected in our gH2AX ChIP-Seq experiments. We found that cells lacking or having impaired MLL2 were presenting statistically signifficant, higher levels of mutations at the tested genes as compared to their parental controls. The experiments were performed using human and mouse cells. For the human cells, the parental HCT116 cells were used as control. Two different MLL2 KO clones (KO19 and KO34) and a DSET MLL2 cell line were employed. For the mouse cells, the F/F cells were used, in which both MLL2 alleles are targeted by loxp. Tamoxifen treatment for 24 hours results in the excision of both MLL2 alleles (FC/FC cells). F/F cells were treated with tamoxifen (FC/FC) or vehicle (DMSO, F/F) for 24 hours. Half of the cells were then harvested and used as controls (T0), while the other half were cultured for another 30 days (T30). Mutations after 30 days (T30) of tamoxifen/vehicle treatment were measured compared to the T0 controls. In all cases, two different pools of primers were employed. All histone genes available to target with high coverage were studied, in either human or mouse cells. For the human cells, 32 histone (HIST1H1A HIST1H1B HIST1H1C HIST1H1D HIST1H1E HIST1H1T HIST1H2AC HIST1H2AD HIST1H2AG HIST1H2AH HIST1H2AI HIST1H2AJ HIST1H2AK HIST1H2BF HIST1H2BG HIST1H2BH HIST1H2BI HIST1H2BJ HIST1H2BK HIST1H2BN HIST1H3B HIST1H3C HIST1H3D HIST1H3E HIST1H3F HIST1H3G HIST1H3H HIST1H3I HIST1H4B HIST1H4F HIST1H4J HIST2H2AC) and 6 other genes (BTG2 SGK1 MDM2 CDKN1A EGR1 RPLP0) were targeted. For the mouse cells, 21 histone (HIST1H1A HIST1H1B HIST1H1C HIST1H1D HIST1H1E HIST1H1T HIST1H2AK HIST1H2BQ HIST1H3B HIST1H3C HIST1H3F HIST1H4F HIST1H4J HIST1H4N HIST1H4N HIST2H2AA1 HIST2H2AA1 HIST2H2AA2 HIST2H2AA2 HIST2H2AC HIST2H2BB) and 6 other genes (BTG2 SGK1 MDM2 CDKN1A EGR1 RPLP0) were targeted. Processed data to be submitted to appropriate variation archive.
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