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

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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.

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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.
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.
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.
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.
Christopher Chen

Department of Biomedical Engineering, Boston University, Boston, United States

Competing interests
The authors declare that no competing interests exist.
David 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.

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