Systematic in vivo structure-function analysis of p300 in hematopoiesis

Erin A. Kimbrel, Madeleine E. Lemieux, Xiaobo Xia, Tina N. Davis, Vivienne I. Rebel, Andrew L. Kung

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Cyclic adenosine monophosphate response element binding (CREB) - binding protein (CBP) and p300 are multidomain transcriptional coactivators that help assemble large regulatory complexes at sites of active transcription. Nullizygosity of CBP or p300 results in pervasive defects in hematopoiesis. To systematically assess the structural domains of p300 required for normal hematopoiesis, we used recombinase-mediated cassette exchange to create an allelic series of coisogenic embryonic stem cells, each expressing a different mutant of p300 from the endogenous locus. We found that deletion of either the KIX or CH1 domain caused profound and pervasive defects in hematopoiesis, whereas the loss of most other domains had only lineage-restricted effects. When expressed from the p300 locus, an extra copy of CBP largely compensated for a lack of p300. Surprisingly, mutation of the p300 histone acetyltransferase (HAT) domain had minimal effects on hematopoiesis, and actually increased progenitor and stem cell numbers and proliferative potential. Our results suggest that, in distinct contrast to other organ systems, HAT activity does not provide a critical function for hematopoietic development and emphasizes the importance of enzyme-independent functions of p300.

Original languageEnglish (US)
Pages (from-to)4804-4812
Number of pages9
JournalBlood
Volume114
Issue number23
DOIs
StatePublished - Nov 26 2009

Fingerprint

CREB-Binding Protein
Histone Acetyltransferases
Hematopoiesis
Stem cells
Defects
Recombinases
Response Elements
Transcription
Cyclic AMP
Carrier Proteins
Stem Cells
Enzymes
Embryonic Stem Cells
Catalytic Domain
Cell Count
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Kimbrel, E. A., Lemieux, M. E., Xia, X., Davis, T. N., Rebel, V. I., & Kung, A. L. (2009). Systematic in vivo structure-function analysis of p300 in hematopoiesis. Blood, 114(23), 4804-4812. https://doi.org/10.1182/blood-2009-04-217794

Systematic in vivo structure-function analysis of p300 in hematopoiesis. / Kimbrel, Erin A.; Lemieux, Madeleine E.; Xia, Xiaobo; Davis, Tina N.; Rebel, Vivienne I.; Kung, Andrew L.

In: Blood, Vol. 114, No. 23, 26.11.2009, p. 4804-4812.

Research output: Contribution to journalArticle

Kimbrel, EA, Lemieux, ME, Xia, X, Davis, TN, Rebel, VI & Kung, AL 2009, 'Systematic in vivo structure-function analysis of p300 in hematopoiesis', Blood, vol. 114, no. 23, pp. 4804-4812. https://doi.org/10.1182/blood-2009-04-217794
Kimbrel EA, Lemieux ME, Xia X, Davis TN, Rebel VI, Kung AL. Systematic in vivo structure-function analysis of p300 in hematopoiesis. Blood. 2009 Nov 26;114(23):4804-4812. https://doi.org/10.1182/blood-2009-04-217794
Kimbrel, Erin A. ; Lemieux, Madeleine E. ; Xia, Xiaobo ; Davis, Tina N. ; Rebel, Vivienne I. ; Kung, Andrew L. / Systematic in vivo structure-function analysis of p300 in hematopoiesis. In: Blood. 2009 ; Vol. 114, No. 23. pp. 4804-4812.
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