MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters.

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 Res

journal_title

Nucleic acids research

authors

Okuda H,Kawaguchi M,Kanai A,Matsui H,Kawamura T,Inaba T,Kitabayashi I,Yokoyama A

doi

10.1093/nar/gkt1394

subject

Has Abstract

pub_date

2014-04-01 00:00:00

pages

4241-56

issue

7

eissn

0305-1048

issn

1362-4962

pii

gkt1394

journal_volume

42

pub_type

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