Extensive chromatin remodelling and establishment of transcription factor ‘hotspots’ during early adipogenesis

The EMBO Journal (2011) 30, 1459 - 1472 doi:10.1038/emboj.2011.65
Published online: 22 March 2011


Subject Category: Chromatin and Transcription
Extensive chromatin remodelling and establishment of transcription factor ‘hotspots’ during early adipogenesis

Rasmus Siersbæk1, Ronni Nielsen1, Sam John2, Myong-Hee Sung2, Songjoon Baek2, Anne Loft1, Gordon L Hager2 and Susanne Mandrup1

Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Correspondence to:
Susanne Mandrup, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark. Tel.: +45 6550 2340; Fax: +45 6550 2467; E-mail: s.mandrup@bmb.sdu.dk

Gordon L Hager, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-5055, USA. Tel.: +1 301 496 9867; Fax: +1 301 496 4951; E-mail: hagerg@dce41.nci.nih.gov

Received 30 September 2010; Accepted 17 February 2011

Adipogenesis is tightly controlled by a complex network of transcription factors acting at different stages of differentiation. Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein (C/EBP) family members are key regulators of this process. We have employed DNase I hypersensitive site analysis to investigate the genome-wide changes in chromatin structure that accompany the binding of adipogenic transcription factors. These analyses revealed a dramatic and dynamic modulation of the chromatin landscape during the first hours of adipocyte differentiation that coincides with cooperative binding of multiple early transcription factors (including glucocorticoid receptor, retinoid X receptor, Stat5a, C/EBPβ and -δ) to transcription factor ‘hotspots’. Our results demonstrate that C/EBPβ marks a large number of these transcription factor ‘hotspots’ before induction of differentiation and chromatin remodelling and is required for their establishment. Furthermore, a subset of early remodelled C/EBP-binding sites persists throughout differentiation and is later occupied by PPARγ, indicating that early C/EBP family members, in addition to their well-established role in activation of PPARγ transcription, may act as pioneering factors for PPARγ binding.