Abstract:
:Mixed-lineage leukemia (MLL) maintains the expression of cellular memory genes during development, while leukemic MLL fusion proteins aberrantly maintain expression of hematopoietic stem cell program genes such as HOXA9 to cause leukemia. However, the molecular mechanism of gene activation is unclear. Here we show that only two functional modules are necessary and sufficient for target recognition: those that bind to non-methylated CpGs and di-/tri-methylated histone H3 lysine 36 (H3K36me2/3). An artificial protein composed of the two targeting modules and an interaction domain for AF4-family coactivators can functionally substitute for MLL fusion proteins. Because H3K36me2/3 markers are indicative of active transcription, MLL fusion proteins target previously active CpG-rich genes and activate transcription by recruiting coactivators thereto. Our results indicate that such chromatin context-dependent gene activation is the fundamental mechanism by which MLL fusion proteins maintain the expression of the cellular memory/hematopoietic stem cell program genes.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Okuda H,Kawaguchi M,Kanai A,Matsui H,Kawamura T,Inaba T,Kitabayashi I,Yokoyama Adoi
10.1093/nar/gkt1394subject
Has Abstractpub_date
2014-04-01 00:00:00pages
4241-56issue
7eissn
0305-1048issn
1362-4962pii
gkt1394journal_volume
42pub_type
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