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CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation

Lawryn H Kasper1, Stephanie Lerach, Jianmin Wang

  • 1Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

The EMBO Journal
|September 23, 2010
PubMed

Insights

The number of CREB-binding sites (CREs) influences gene transcription dependence on histone acetyltransferases CBP and p300. Genes with more CREs and coactivators like CRTC2 show resilient expression, suggesting coactivator availability tunes gene patterns.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Epigenetics

Background:

  • The influence of DNA sequence on mammalian gene transcription in response to extracellular signals is not fully understood.
  • Histone acetyltransferases (HATs) like CREB-binding protein (CBP) and p300 play crucial roles in gene regulation.
  • CREB-binding sites (CREs) are key DNA elements involved in transcriptional control.

Purpose of the Study:

  • To investigate how the number of CREB-binding sites (CREs) in mammalian genes affects their transcriptional response to extracellular signals.
  • To determine the role of CBP and p300 in endogenous gene transcription based on CREs and coactivator presence.
  • To elucidate the mechanisms by which gene expression resilience is achieved in the absence of CBP/p300.

Main Methods:

  • Utilizing fibroblasts with knocked-out CBP and p300 to assess histone H4 acetylation and gene transcription.
  • Comparing transcriptional responses between reporter plasmids and endogenous genes.
  • Analyzing the correlation between gene transcription, CREs, CREB binding, and CRTC2 levels in CBP/p300 null cells.

Main Results:

  • Fibroblasts lacking CBP and p300 exhibited attenuated histone H4 acetylation at CREB-target genes upon cyclic-AMP stimulation, but transcription was not uniformly inhibited.
  • Dependence on CBP/p300 varied significantly between reporter plasmids and endogenous genes.
  • Transcription in CBP/p300 null cells correlated with a higher number of CREs, increased CREB binding, and greater CRTC2 presence, with CRTC2 rescuing or contributing to cAMP-inducible expression.

Conclusions:

  • Endogenous genes with a higher concentration and diversity of coactivators, such as CRTC2, demonstrate more resilient inducible expression.
  • Coactivator availability, rather than solely signal input or transcription factor levels, can tune gene expression patterns.
  • The number of CREs and associated coactivators can dictate the requirement for HATs like CBP and p300 in gene transcription.

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