Atf4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis

Daniel M. Cohen, Kyoung Jae Won, Nha Nguyen, Mitchell A. Lazar, Christopher S. Chen, David J. Steger

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

A well-established cascade of transcription factor (TF) activity orchestrates adipogenesis in response to chemical cues, yet how cell-intrinsic determinants of differentiation such as cell shape and/or seeding density inform this transcriptional program remain enigmatic. Here, we uncover a novel mechanism licensing transcription in human mesenchymal stem cells (hMSCs) adipogenically primed by confluence. Prior to adipogenesis, confluency promotes heterodimer recruitment of the bZip TFs C/EBPβ and ATF4 to a non-canonical C/EBP DNA sequence. ATF4 depletion decreases both cell-density-dependent transcription and adipocyte differentiation. Global profiling in hMSCs and a novel cell-free assay reveals that ATF4 requires C/EBPβ for genomic binding at a motif distinct from that bound by the C/EBPβ homodimer. Our observations demonstrate that C/EBPβ bridges the transcriptional programs in na¨ıve, confluent cells and early differentiating preadipocytes. Moreover, they suggest that homo- and heterodimer formation poise C/EBPβ to execute diverse and stage-specific transcriptional programs by exploiting an expanded motif repertoire.

Original languageEnglish (US)
Article numbere06821
Pages (from-to)1-20
Number of pages20
JournaleLife
Volume4
Issue numberJUNE 2015
DOIs
StatePublished - Jun 25 2015

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cohen, D. M., Won, K. J., Nguyen, N., Lazar, M. A., Chen, C. S., & Steger, D. J. (2015). Atf4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis. eLife, 4(JUNE 2015), 1-20. [e06821]. https://doi.org/10.7554/eLife.06821.001