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| Status |
Public on Jul 01, 2017 |
| Title |
Vitamin C induced epigenomic remodeling in IDH1 mutant acute myeloid leukemia |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
|
| Summary |
The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating TET2 mutations and neomorphic IDH mutations are recurrent and mutually exclusive in acute myeloid leukemia (AML) genomes. Ascorbic Acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukemic model expressing IDH1R132H. Vitamin C treatment induced an IDH1R132H dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation. Vitamin C induced differentially methylated regions (DMRs) that displayed a significant overlap with enhancers implicated in myeloid differentiation and were enriched in sequence elements for the hematopoietic transcription factors RUNX1 and PU.1. ChIP-seq of PU.1 and RUNX1 revealed a significant loss of PU.1 and increase of RUNX1 bound DNA elements accompanied by their demethylation following vitamin C treatment. Additionally, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. Based on these data we propose a model of vitamin C induced epigenetic remodelling of transcription factor binding sites driving differentiation in a leukemic model.
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| Overall design |
We describe the distribution of 5mC, 5hmC H3K4me1, H3K4me3, H3K27ac, Runx1 and PU.1 as well as the transcriptional profile of HOXA9 immortalized mouse bone marrow cells expressing IDH1 R132H mutant (and IDH1 wt for medip/hmedip)
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| Contributor(s) |
Mingay M, Hirst M |
| Citation(s) |
28663574 |
| Submission date |
Oct 05, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Martin Hirst |
| E-mail(s) |
mhirst@bcgsc.ca
|
| Phone |
604-822-6373
|
| Organization name |
University of British Columbia
|
| Department |
Department of Microbiology & Immunology
|
| Street address |
2125 East Mall
|
| City |
Vancouver |
| State/province |
British Columbia |
| ZIP/Postal code |
V6T 1Z4 |
| Country |
Canada |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA345426 |
| SRA |
SRP090852 |
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