Transcriptomics

Dataset Information

300

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


ABSTRACT: 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

ORGANISM(S): Mus musculus  

SUBMITTER: Christopher Vakoc   Shinpei Kawaoka 

PROVIDER: E-GEOD-43725 | ArrayExpress | 2013-02-19

SECONDARY ACCESSION(S): SRP018248GSE43725PRJNA187484

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia.

Wang Eric E   Kawaoka Shinpei S   Yu Ming M   Shi Junwei J   Ni Ting T   Yang Wenjing W   Zhu Jun J   Roeder Robert G RG   Vakoc Christopher R CR  

Proceedings of the National Academy of Sciences of the United States of America 20130214 10


Mixed-lineage leukemia (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 ring finger protein 20 (RNF20) as an  ...[more]

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