Transcriptional and epigenetic regulation of the GM-CSF promoter by RUNX1.
The RUNX1 gene, which is essential for normal hematopoiesis, is frequently rearranged by the t(8;21) chromosomal translocation in acute myeloid leukemia. The resulting RUNX1-ETO fusion protein contributes to leukemic progression by directing aberrant association of transcriptional cofactors and epigenetic modifiers to RUNX1 target genes. For example, the GM-CSF gene is activated by RUNX1, but is repressed by RUNX1-ETO. Here we show that RUNX1 normally cooperates with the histone acetyltransferase, CBP, to regulate GM-CSF expression at two levels. Firstly, it directs the establishment of a competent chromatin environment at the GM-CSF promoter prior to gene activation. It then participates in the transcriptional activation of the promoter in response to immune stimuli. In contrast, RUNX1-ETO, which cannot associate with CBP, is unable to transactivate the GM-CSF promoter and is associated with the generation of a repressive chromatin environment at the promoter.
Oakford
Phillippa C
PC
Menzies Research Institute, University of Tasmania, Tasmania, Australia.
James
Sally R
SR
Qadi
Abeer
A
West
Alison C
AC
Ray
Shannon N
SN
Bert
Andrew G
AG
Cockerill
Peter N
PN
Holloway
Adele F
AF
D001483:Base Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D017931:DNA Primers; D044127:Epigenesis, Genetic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D014158:Transcription, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D034741:RNA, Small Interfering; C493728:RUNX1 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor