E-GEOD-43725 - The histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia

Status
Released on 19 February 2013, last updated on 14 March 2013
Organism
Mus musculus
Samples (3)
Protocols (4)
Description
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. Examination of gene expression profiles upon RNF20 RNAi in MLL-AF9 acute myeloid leukemia cells
Experiment type
RNA-seq of coding RNA 
Contacts
Christopher Vakoc, Shinpei Kawaoka
Citation
Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia. Wang E, Kawaoka S, Yu M, Shi J, Ni T, Yang W, Zhu J, Roeder RG, Vakoc CR. , Europe PMC 23412334
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
Files
Investigation descriptionE-GEOD-43725.idf.txt
Sample and data relationshipE-GEOD-43725.sdrf.txt
Processed data (1)E-GEOD-43725.processed.1.zip
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