Molecular architecture of transcription factor hotspots in early adipogenesis

TY - JOUR

T1 - Molecular architecture of transcription factor hotspots in early adipogenesis

AU - Siersbæk, Rasmus

AU - Baek, Songjoon

AU - Rabiee, Atefeh

AU - Nielsen, Ronni

AU - Traynor, Sofie

AU - Clarke, Nicholas

AU - Sandelin, Albin Gustav

AU - Jensen, Ole N.

AU - Sung, Myong-Hee

AU - Hager, Gordon L.

AU - Mandrup, Susanne

N1 - Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2014/6/12

Y1 - 2014/6/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2014.04.043

DO - 10.1016/j.celrep.2014.04.043

M3 - Journal article

C2 - 24857666

SN - 2211-1247

VL - 7

SP - 1434

EP - 1442

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -