E2A proteins enhance the histone acetyltransferase activity of the transcriptional co-activators CBP and p300

Biochim Biophys Acta. 2012 May;1819(5):446-53. doi: 10.1016/j.bbagrm.2012.02.009. Epub 2012 Feb 22.

Abstract

The E2A gene encodes the E-protein transcription factors E12 and E47 that play critical roles in B-lymphopoiesis. A somatic chromosomal translocation detectable in 5% of cases of acute lymphoblastic leukemia (ALL) involves E2A and results in expression of the oncogenic transcription factor E2A-PBX1. CREB binding protein (CBP) and its close paralog p300 are transcriptional co-activators with intrinsic histone acetyltransferase (HAT) activity. We and others have shown that direct binding of an N-terminal transcriptional activation domain present in E12/E47 and E2A-PBX1 to the KIX domain of CBP/p300 contributes to E2A protein function. In the current work we show for the first time that the catalytic HAT activity of CBP/p300 is increased in the presence of residues 1-483 of E2A (i.e., the portion present in E2A-PBX1). The addition of purified, recombinant E2A protein to in vitro assays results in a two-fold augmentation of CBP/p300 HAT activity, whereas in vivo assays show a ten-fold augmentation of HAT-dependent transcriptional induction and a five-fold augmentation of acetylation of reporter plasmid-associated histone by CBP in response to co-transfected E2A. Our results indicate that the HAT-enhancing effect is independent of the well-documented E2A-CBP interaction involving the KIX domain and suggest a role for direct, perhaps low affinity binding of E2A to a portion of CBP that includes the HAT domain and flanking elements. Our findings add to a growing body of literature indicating that interactions between CBP/p300 and transcription factors can function in a specific manner to modulate HAT catalytic activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Basic Helix-Loop-Helix Transcription Factors* / genetics
  • Basic Helix-Loop-Helix Transcription Factors* / metabolism
  • Binding Sites
  • CREB-Binding Protein* / genetics
  • CREB-Binding Protein* / metabolism
  • HEK293 Cells
  • Histone Acetyltransferases / metabolism*
  • Homeodomain Proteins / metabolism
  • Humans
  • Oncogene Proteins, Fusion / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Transcriptional Activation
  • p300-CBP Transcription Factors* / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Oncogene Proteins, Fusion
  • TCF3 protein, human
  • E2A-Pbx1 fusion protein
  • CREB-Binding Protein
  • CREBBP protein, human
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor