MOZ-TIF2 alters cofactor recruitment and histone modification at the RARbeta2 promoter: differential effects of MOZ fusion proteins on CBP- and MOZ-dependent activators.
MOZ-TIF2 and MOZ-CBP are leukemogenic fusion proteins associated with therapy-induced acute myeloid leukemia. These proteins are thought to subvert normal gene expression in differentiating hematopoietic progenitor cells. We have previously shown that MOZ-TIF2 inhibits transcription by CREB-binding protein (CBP)/p300-dependent activators such as nuclear receptors and p53. Here we have shown that MOZ-TIF2 associates with the RARbeta2 promoter in vivo, resulting in altered recruitment of CBP/p300, aberrant histone modification, and down-regulation of the RARbeta2 gene. In contrast, MOZ-TIF2 up-regulated transcription mediated by the MOZ/MYST3-dependent activator AML1/RUNX1. Both wild type MOZ and MOZ-TIF2 were found to colocalize with AML1, and MOZ-TIF2 was recruited to an AML1 target promoter. A MOZ-CBP fusion protein showed similar functions to MOZ-TIF2 in that it inhibited retinoic acid receptor-mediated transcription but enhanced AML1 reporter activation. Although it contains almost the entire CBP sequence, MOZ-CBP does not appear to associate with PML bodies. In summary, our results indicate that leukemogenic MOZ fusion proteins have differential effects on the activities of CBP-dependent and MOZ-dependent activators because of their ability to alter cofactor recruitment and chromatin modification at target promoters.
Collins
Hilary M
HM
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
Kindle
Karin B
KB
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
Matsuda
Sachiko
S
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
Ryan
Colm
C
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
Troke
Philip J F
PJF
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
Kalkhoven
Eric
E
Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
Heery
David M
DM
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom. Electronic address: david.heery@nottingham.ac.uk.
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000737:chemistry*; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000502:physiology*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D050880:p300-CBP Transcription Factors / Q000737:chemistry
D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; C475973:MOZ-TIF2 protein, human; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; C082925:retinoic acid receptor beta; D050880:p300-CBP Transcription Factors