title: ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis.
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 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.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cohen
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Nha
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Steger
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D050156:Adipogenesis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017422:Sequence Analysis, DNA
chemical_list: C497109:ATF4 protein, human; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D051701:Activating Transcription Factor 4; D004247:DNA
keywords: adipogenesis; chromosomes; developmental biology; gene expression; genes; human; mouse; stem cells; transcription factors