1. Developmental Biology
  2. Chromosomes and Gene Expression

ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis

  1. Daniel M Cohen
  2. Kyoung-Jae Won
  3. Nha Nguyen
  4. Mitchell A Lazar
  5. Christopher S Chen
  6. David J Steger  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Boston University, United States
https://doi.org/10.7554/eLife.06821
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  1. Daniel M Cohen
  2. Kyoung-Jae Won
  3. Nha Nguyen
  4. Mitchell A Lazar
  5. Christopher S Chen
  6. David J Steger
(2015)
ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis
eLife 4:e06821.
https://doi.org/10.7554/eLife.06821
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Abstract

A well-established cascade of transcription factor 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 transcription factors 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 naïve, confluent cells and early differentiating pre-adipocytes. 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.

Article and author information

Author details

  1. Daniel M Cohen

    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Kyoung-Jae Won

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Nha Nguyen

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Mitchell A Lazar

    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Christopher S Chen

    Department of Biomedical Engineering, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. David J Steger

    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    stegerdj@mail.med.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Fiona M Watt, King's College London, United Kingdom

Version history

  1. Received: February 3, 2015
  2. Accepted: June 25, 2015
  3. Accepted Manuscript published: June 25, 2015 (version 1)
  4. Accepted Manuscript updated: June 26, 2015 (version 2)
  5. Version of Record published: July 15, 2015 (version 3)

Copyright

© 2015, Cohen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Daniel M Cohen
  2. Kyoung-Jae Won
  3. Nha Nguyen
  4. Mitchell A Lazar
  5. Christopher S Chen
  6. David J Steger
(2015)
ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis
eLife 4:e06821.
https://doi.org/10.7554/eLife.06821

Share this article

https://doi.org/10.7554/eLife.06821

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