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| Status |
Public on Nov 15, 2016 |
| Title |
Epigenetic regulation of the apoptosis program in t(8;21) AMLs by an AML1-ETO, ERG and RUNX1 triad |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
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| Summary |
The t(8;21) acute myeloid leukemia associated oncoprotein AML1-ETO is a transcription factor that aberrantly regulates the pathways that lead to myeloid differentiation. Here, we set out to investigate the effects of AML1-ETO on gene expression and the epigenome in patient blast cells. We identify two modules, one in which AML1-ETO binds promoter regions of active genes and one represented by non-promoter binding to accessible, yet inactive chromatin regions. Using genome-wide binding analysis and mass spectrometry interaction studies we identify ERG, FLI1, TAL1 and RUNX1 as common binding factors of all AML1-ETO occupied genomic regions, while LYL1 and LMO2 show preferential binding in the context of non promoter regions. Epigenetically, reduced histone acetylation levels at non-promoter regions seems HDAC dependent, as treatment with an HDACi increases acetylation and induces cell death. Both AML1-ETO modules are represented in most aberrantly regulated pathways, including many signaling pathways, self-renewal and apoptosis. For the latter, the expression of the wild type transcription factors RUNX1 and ERG is required, as alterations in expression are associated with the onset of an apoptosis program. Interestingly, upon RUNX1 or ERG knockdown this onset seems to be dependent on increased AML1-ETO expression as combinatorial knockdown of RUNX1/AML1-ETO or ERG/AML1-ETO results in rescue from apoptosis. Together our results show that the balanced interplay of the epigenetic environment and transcription factors retains an anti apoptotic phenotype in t(8;21) AML cells.
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| Overall design |
14 samples for ChIP seq and 2 RNA-seq samples
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| Contributor(s) |
Mandoli A, Singh AA, Oerlemans M, Dirks R, Prange K, Huurne MT, Wierenga B, Janssen-Megens E, Berentsen K, Sharifi N, Kim B, Matarese F, Nguyen LN, Hubner NC, Rao N, Altucci L, Vellenga E, Stunnenberg H, Martens JH |
| Citation(s) |
27851970 |
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| Submission date |
Jan 01, 2016 |
| Last update date |
Nov 11, 2021 |
| Contact name |
Joost Martens |
| E-mail(s) |
joost.martens@ru.nl
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| Phone |
0243780645
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| Organization name |
Radboud University
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| Department |
RIMLS
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| Lab |
Molecular Biology
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| Street address |
Geert Grooteplein 28
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| City |
Nijmegen |
| State/province |
Nederland |
| ZIP/Postal code |
6525GA |
| Country |
Netherlands |
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| Platforms (2) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA307457 |
| SRA |
SRP068016 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE76464_RAW.tar |
415.2 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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