H2A.Z-dependent crosstalk between enhancer and promoter regulates cyclin D1 expression

Oncogene. 2013 Sep 5;32(36):4243-51. doi: 10.1038/onc.2012.442. Epub 2012 Oct 29.


H2A.Z association with specific genomic loci is thought to contribute to a chromatin structure that promotes transcription activation. Acetylation of H2A.Z at promoters of oncogenes has been linked to tumorigenesis. The mechanism is unknown. Here, we show that in triple negative breast cancer cells, H2A.Z bound to the promoter of the constitutively, weakly expressed cyclin D1 oncogene (CCND1), a key regulator of cellular proliferation. Depleting the pool of H2A.Z stimulated transcription of CCND1 in the absence of its cognate transcription factor, the estrogen receptor (ER). During activation of CCND1, H2A.Z was released from the transcription start site (TSS) and downstream enhancer (enh2) sequences. Concurrently, acetylation of H2A.Z, H3 and H4 at the TSS was increased but only H2A.Z was acetylated at enh2. Acetylation of H2A.Z required the Tip60 acetyltransferase to be associated with the activated CCND1 on both TSS and enh2 sites. Depletion of Tip60 prevented CCND1 activation. Chromosome conformation capture experiments (3C) revealed specific contacts between the TSS and enh2 chromatin regions. These results suggest that release of a histone H2A.Z-mediated repression loop activates CCND1 for transcription. Our findings open new avenues for controlling and understanding aberrant gene expression associated with tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Line, Tumor
  • Chromatin / genetics
  • Chromatin / metabolism
  • Cyclin D1 / genetics*
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation*
  • Histone Acetyltransferases / metabolism
  • Histones / metabolism*
  • Humans
  • Lysine Acetyltransferase 5
  • Models, Biological
  • Nucleic Acid Conformation
  • Promoter Regions, Genetic*
  • Transcriptional Activation


  • Chromatin
  • Histones
  • histone H2A.F-Z
  • Cyclin D1
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5