Cohen, Daniel MWon, Kyoung-JaeNguyen, NhaLazar, Mitchell AChen, ChristopherSteger, David J2015-08-032015Cohen, Daniel M, Kyoung-Jae Won, Nha Nguyen, Mitchell A Lazar, Christopher S Chen, and David J Steger. 2015. “ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis.” eLife 4 (1): e06821. doi:10.7554/eLife.06821. http://dx.doi.org/10.7554/eLife.06821.2050-084Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17820960A 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 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. DOI: http://dx.doi.org/10.7554/eLife.06821.001en-USadipogenesistranscription factorsgene expressionhumanmouseJournal Article2015-08-0310.7554/eLife.06821