C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment

Christine Yeamans, Dehua Wang, Ido Paz Priel, Bruce E. Torbett, Daniel G. Tenen, Alan D. Friedman

Research output: Contribution to journalArticlepeer-review

Abstract

The PU.1 gene contains a 237-base pair distal enhancer located 14 kilobases upstream of its promoter. We have identified 2 sites within the PU.1 enhancer that strongly bind C/EBPα in a gel shift assay, and interaction with endogenous C/EBPα was confirmed by chromatin immunoprecipitation. Mutation of these DNA elements reduced activity of a distal enhancer-promoter construct 2- or 5-fold in a myeloid cell line, while mutation of a weaker C/EBPα-binding site located in the promoter minimally reduced activity in this context. These findings strengthen the link between C/EBPα and PU.1 expression. Reduction of C/EBPα activity in cases of acute myeloid leukemia may therefore contribute to transformation by reducing PU.1 levels. In addition, induction of PU.1 by C/EBPα during normal hematopoiesis may contribute to stem cell commitment to the myeloid lineages and further commitment to monopoiesis. Consistent with a requirement for C/EBPα induction of PU.1 during myeloid development, we demonstrate that C/EBPα induces monocytic development when expressed in PU.1+/+, PU.1 +/-, or PU.1+/kd marrow myeloid progenitors but induces granulocyte lineage commitment in PU.1kd/kd cells lacking the PU.1 distal enhancer and does not induce either lineage in PU.1-/- cells.

Original languageEnglish (US)
Pages (from-to)3136-3142
Number of pages7
JournalBlood
Volume110
Issue number9
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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