biomedical and healthCAre Data Discovery Index Ecosystem
biomedical and healthCAre Data Discovery Index Ecosystem
| Title: | Site- and allele-specific de-silencing of polycomb repressive activity by insertional oncogenesis: a new recurrent mechanism of TAL1 activation in T-ALL
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| dateReleased: |
07-10-2014
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| description: |
T-cell acute lymphoblastic leukemia’s (T-ALL) are malignant proliferations of thymocytes occurring through a large diversity of genomic and epigenetic alteration. TAL1 is amongst the most frequently deregulated oncogenes. Known TAL1 dysregulation mechanisms consist of t(1;14) translocations and SIL-TAL deletions. Yet, over half of TAL1+ cases lack TAL1 lesions, pointing to unrecognized (epi)genetic deregulation mechanisms. In such “unresolved cases”, TAL1 expression can be mono-allelic, compatible with a direct alteration in cis within or around the TAL1 gene, or bi-allelic, likely reflecting indirect deregulation in trans. Using ChIP-seq, we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3 repressive mark is focally diminished in TAL1+ T-ALLs. Sequencing revealed that >20% of mono-allelic TAL1+ patients without previously known alterations display micro-insertions or RAG1/2-mediated episomal reintegration in a single site 5’ to TAL1. Using “allelic-ChIP” and CrispR assays, we demonstrate that such insertions induce selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies reveal a new adverse mechanism of mono-allelic oncogenic activation through site-specific epigenetic de-silencing. ChIP-seq experiments were designed to asses the dynamic enrichment of H3K27me3 and H3K27ac marks on the genome and understand the mechanisms underlying the TAL1 expression cys-regulation.
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| privacy: |
not applicable
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| aggregation: |
instance of dataset
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| ID: |
E-GEOD-59257
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| refinement: |
raw
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| alternateIdentifiers: |
59257
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| keywords: |
functional genomics
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| dateModified: |
08-14-2014
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| availability: |
available
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| types: |
gene expression
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| name: |
Homo sapiens
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| accessURL: | https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-59257/E-GEOD-59257.raw.1.zip |
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gzip compressed
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TXT
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| accessType: |
download
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| authentication: |
none
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| authorization: |
none
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| accessURL: | https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-59257/E-GEOD-59257.processed.1.zip |
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ArrayExpress
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gzip compressed
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TXT
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| accessType: |
download
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| authentication: |
none
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| authorization: |
none
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| accessURL: | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE59257 |
| storedIn: |
Gene Expression Omnibus
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| qualifier: |
not compressed
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| format: |
HTML
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| accessType: |
landing page
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| primary: |
true
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| authentication: |
none
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| authorization: |
none
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| abbreviation: |
EBI
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| homePage: | http://www.ebi.ac.uk/ |
| ID: |
SCR:004727
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| name: |
European Bioinformatics Institute
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| homePage: | https://www.ebi.ac.uk/arrayexpress/ |
| ID: |
SCR:002964
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| name: |
ArrayExpress
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