Modulation of vitamin D signaling by the pioneer factor CEBPA

Biochim Biophys Acta Gene Regul Mech. 2019 Jan;1862(1):96-106. doi: 10.1016/j.bbagrm.2018.12.004. Epub 2018 Dec 11.


The myeloid master regulator CCAAT enhancer-binding protein alpha (CEBPA) is known as a pioneer factor. In this study, we report the CEBPA cistrome of THP-1 human monocytes after stimulation with the vitamin D receptor (VDR) ligand 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) for 2, 8 and 24 h. About a third of the genomic VDR binding sites co-located with those of CEBPA. In parallel, the binding strength of 5% of the CEBPA cistrome, i.e. some 1500 sites, is significantly (p < 0.001) affected by 1,25(OH)2D3. Transcriptome-wide analysis after CEBPA silencing indicated that the pioneer factor enhances both the basal expression and ligand inducibility of 70 vitamin D target genes largely involved in lipid signaling and metabolism. In contrast, CEBPA suppresses 82 vitamin D target genes many of which are related to the modulation of T cell activity by monocytes. The inducibility of the promoter-specific histone marker H3K4me3 distinguishes the former class of genes from the latter. Moreover, prominent occupancy of the myeloid pioneer factor PU.1 on 1,25(OH)2D3-sensitive CEBPA enhancers mechanistically explains the dichotomy of vitamin D target genes. In conclusion, CEBPA supports vitamin D signaling concerning actions of the innate immune system, but uses the antagonism with PU.1 for suppressing possible overreactions of adaptive immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • CCAAT-Enhancer-Binding Proteins / physiology*
  • Humans
  • Immunity, Innate
  • Monocytes / metabolism
  • Proto-Oncogene Proteins / physiology
  • Receptors, Calcitriol / metabolism*
  • Signal Transduction
  • THP-1 Cells
  • Trans-Activators / physiology
  • Vitamin D / analogs & derivatives*
  • Vitamin D / metabolism


  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Proto-Oncogene Proteins
  • Receptors, Calcitriol
  • Trans-Activators
  • VDR protein, human
  • dihydroxy-vitamin D3
  • proto-oncogene protein Spi-1
  • Vitamin D