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| Status |
Public on Jul 10, 2014 |
| Title |
Site- and allele-specific de-silencing of polycomb repressive activity by insertional oncogenesis: a new recurrent mechanism of TAL1 activation in T-ALL |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
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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| Contributor(s) |
Navarro J, Touzart A, Pradel LC, Loosveld M, Koubi M, Fenouil R, Le Noir S, Ahmad Maqbool M, Morgado E, Gregoire C, Jaeger S, Mamessier E, Pignon C, Hacein-Bey S, Malissen B, Gut M, Gut IG, Dombret H, Macintyre EA, Howe S, Thrasher A, Ifrah N, Payet-Bornet D, Duprez E, Andrau J, Asnafi V, Nadel B |
| Citation missing |
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| Submission date |
Jul 09, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Romain Fenouil |
| Organization name |
CNRS
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| Department |
CIML
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| Lab |
CB2M
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| Street address |
Parc Scientifique et Technologique de Luminy - Case 906
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| City |
Marseille |
| State/province |
F13288 Cedex 09 |
| ZIP/Postal code |
13009 |
| Country |
France |
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| Platforms (1) |
| GPL9115 |
Illumina Genome Analyzer II (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA254813 |
| SRA |
SRP044191 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE59257_RAW.tar |
833.1 Mb |
(http)(custom) |
TAR (of WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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