title: Molecular architecture of transcription factor hotspots in early adipogenesis.
abstract: Transcription factors have recently been shown to colocalize in hotspot regions of the genome, which are further clustered into super-enhancers. However, the detailed molecular organization of transcription factors at hotspot regions is poorly defined. Here, we have used digital genomic footprinting to precisely define factor localization at a genome-wide level during the early phase of 3T3-L1 adipocyte differentiation, which allows us to obtain detailed molecular insight into how transcription factors target hotspots. We demonstrate the formation of ATF-C/EBP heterodimers at a composite motif on chromatin, and we suggest that this may be a general mechanism for integrating external signals on chromatin. Furthermore, we find evidence of extensive recruitment of transcription factors to hotspots through alternative mechanisms not involving their known motifs and demonstrate that these alternative binding events are functionally important for hotspot formation and activity. Taken together, these findings provide a framework for understanding transcription factor cooperativity in hotspots.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Siersbæk
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Songjoon
authors.initials: S
authors.lastname: Baek
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Rabiee
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Ronni
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Sofie
authors.initials: S
authors.lastname: Traynor
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Clark
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Albin
authors.initials: A
authors.lastname: Sandelin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Ole N
authors.initials: ON
authors.lastname: Jensen
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Myong-Hee
authors.initials: MH
authors.lastname: Sung
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark. Electronic address: s.mandrup@bmb.sdu.dk.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D016475:3T3 Cells; D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics; D018983:DNA Footprinting; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D051379:Mice; D059372:Nucleotide Motifs; D011485:Protein Binding; D015533:Transcriptional Activation
chemical_list: D051696:Activating Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D002843:Chromatin