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| Status |
Public on Feb 19, 2013 |
| Title |
The histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
MLL-fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here we identify the histone H2B E3 ubiquitin ligase RNF20 as an additional requirement for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation; under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, including Hoxa9 and Meis1; effects that resemble Dot1l-inhibition. Using ChIP-seq, we found that H2B ubiquitination (H2Bub) is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, we found that Rnf20 is required to maintain local levels of H3K79 di-methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby co-transcriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program.
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| Overall design |
Examination of gene expression profiles upon RNF20 RNAi in MLL-AF9 acute myeloid leukemia cells
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| Contributor(s) |
Kawaoka S, Vakoc C |
| Citation(s) |
23412334 |
| Submission date |
Jan 24, 2013 |
| Last update date |
May 15, 2019 |
| Contact name |
Shinpei Kawaoka |
| E-mail(s) |
skawaoka@cshl.edu
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| Phone |
631-327-4269
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| Organization name |
Cold Spring Harbor Laboratory
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| Street address |
1 Bungtown road
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| City |
Cold Spring Harbor |
| ZIP/Postal code |
11724 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA187484 |
| SRA |
SRP018248 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE43725_RAW.tar |
740.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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