Epigenetic consequences of AML1-ETO action at the human c-FMS locus.
Although many leukaemia-associated nuclear oncogenes are well characterized, little is known about the molecular details of how they alter gene expression. Here we examined transcription factor complexes and chromatin structure of the human c-FMS gene in normal and leukaemic cells. We demonstrate by in vivo footprinting and chromatin immunoprecipitation assays that this gene is bound by the transcription factor AML1 (RUNX1). In t(8;21) leukaemic cells expressing the aberrant fusion protein AML1-ETO, we demonstrate that this protein is part of a transcription factor complex binding to extended sequences of the c-FMS intronic regulatory region rather than the promoter. The AML1-ETO complex does not disrupt binding of other transcription factors, indicating that c-FMS is not irreversibly epigenetically silenced. However, AML1-ETO binding correlates with changes in the histone modification pattern and increased association of histone deacetylases. Our experiments provide for the first time a direct insight into the chromatin structure of an AML1-ETO-bound target gene.
Follows
George A
GA
Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK.
Tagoh
Hiromi
H
Lefevre
Pascal
P
Hodge
Donald
D
Morgan
Gareth J
GJ
Bonifer
Constanze
C
D000208:Acute Disease; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D015870:Gene Expression; D020868:Gene Silencing; D016236:Genes, fms; D018922:HL-60 Cells; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007438:Introns; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases