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

TY - JOUR

T1 - ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis

AU - Cohen, Daniel M

AU - Won, Kyoung-Jae

AU - Nguyen, Nha

AU - Lazar, Mitchell A

AU - Chen, Christopher S

AU - Steger, David J

PY - 2015/6/25

Y1 - 2015/6/25

N2 - 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.

AB - 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.

KW - Activating Transcription Factor 4/metabolism

KW - Adipogenesis

KW - CCAAT-Enhancer-Binding Protein-beta/metabolism

KW - Cell Differentiation

KW - DNA/metabolism

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Humans

KW - Mesenchymal Stromal Cells/metabolism

KW - Molecular Sequence Data

KW - Protein Binding

KW - Sequence Analysis, DNA

U2 - 10.7554/elife.06821

DO - 10.7554/elife.06821

M3 - Journal article

C2 - 26111340

SN - 2050-084X

VL - 4

SP - e06821

JO - eLife

JF - eLife

ER -