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 language | English |
|---|---|
| Journal | eLife |
| Volume | 4 |
| Pages (from-to) | e06821 |
| ISSN | 2050-084X |
| DOIs | |
| Publication status | Published - 25 Jun 2015 |
| Externally published | Yes |
Keywords
- Activating Transcription Factor 4/metabolism
- Adipogenesis
- CCAAT-Enhancer-Binding Protein-beta/metabolism
- Cell Differentiation
- DNA/metabolism
- Gene Expression Profiling
- Gene Expression Regulation
- Humans
- Mesenchymal Stromal Cells/metabolism
- Molecular Sequence Data
- Protein Binding
- Sequence Analysis, DNA