A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis


The coactivators CBP (Cre-element binding protein (CREB)-binding protein) and its paralogue p300 are thought to supply adaptor molecule and protein acetyltransferase functions to many transcription factors that regulate gene expression1. Normal development requires CBP and p300, and mutations in these genes are found in haematopoietic and epithelial tumours2,3,4,5,6. It is unclear, however, which functions of CBP and p300 are essential in vivo. Here we show that the protein-binding KIX domains of CBP and p300 have nonredundant functions in mice. In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb and CREB7,8,9, multilineage defects occur in haematopoiesis, including anaemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis and thrombocytosis. By contrast, age-matched mice homozygous for identical mutations in the KIX domain of CBP are essentially normal. There is a synergistic genetic interaction between mutations in c-Myb and mutations in the KIX domain of p300, which suggests that the binding of c-Myb to this domain of p300 is crucial for the development and function of megakaryocytes. Thus, conserved domains in two highly related coactivators have contrasting roles in haematopoiesis.

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Figure 1: Mouse KIX domain mutations.
Figure 2: Haematopoietic defects in p300KIX/KIX mice.
Figure 3: Mutant CBP and p300 affect CREB and c-Myb.
Figure 4: c-Myb and p300 KIX functionally interact to regulate megakaryocytopoiesis.


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We thank M. Castor, D. Bush, S. Kelly and M. Harper for technical help; J. Gatewood, M. Paktinat, R. Cross, R. Ashmun and A. Hoffmeyer for FACS analyses; S. Steward and T. Pestina for help with the platelet counts; R. Piekorz for assistance with the bone marrow transplants; X. Xiong and J. Schroeder for advice on statistics; A. Hoffmeyer for discussions; R. Shivdasani for advice on purifying megakaryocytes; H. Singh for c-Myb mice; and the Transgenic/Gene Knockout Shared Resource for technical assistance. This work was supported by a grant from the NIH and from the National Cancer Institute Cancer Center Support (CORE) program, and by the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital.

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Correspondence to Paul K. Brindle.

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Kasper, L., Boussouar, F., Ney, P. et al. A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis. Nature 419, 738–743 (2002). https://doi.org/10.1038/nature01062

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