The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements.
The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. Linking regulatory elements to specific promoters genome-wide is currently impeded by the limited resolution of high-throughput chromatin interaction assays. Here we apply a sequence capture approach to enrich Hi-C libraries for >22,000 annotated mouse promoters to identify statistically significant, long-range interactions at restriction fragment resolution, assigning long-range interacting elements to their target genes genome-wide in embryonic stem cells and fetal liver cells. The distal sites contacting active genes are enriched in active histone modifications and transcription factor occupancy, whereas inactive genes contact distal sites with repressive histone marks, demonstrating the regulatory potential of the distal elements identified. Furthermore, we find that coregulated genes cluster nonrandomly in spatial interaction networks correlated with their biological function and expression level. Interestingly, we find the strongest gene clustering in ES cells between transcription factor genes that control key developmental processes in embryogenesis. The results provide the first genome-wide catalog linking gene promoters to their long-range interacting elements and highlight the complex spatial regulatory circuitry controlling mammalian gene expression.
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Stefan
S
Schoenfelder
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Mayra
M
Furlan-Magaril
University College London, UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom; Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
Borbala
B
Mifsud
University College London, UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom; Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
Filipe
F
Tavares-Cadete
Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom; EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom;
Robert
R
Sugar
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Biola-Maria
BM
Javierre
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Takashi
T
Nagano
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada;
Yulia
Y
Katsman
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada;
Moorthy
M
Sakthidevi
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom; Bioinformatics Group, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Steven W
SW
Wingett
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Emilia
E
Dimitrova
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Andrew
A
Dimond
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Lucas B
LB
Edelman
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Sarah
S
Elderkin
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Kristina
K
Tabbada
University College London, UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom; Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
Elodie
E
Darbo
Bioinformatics Group, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Simon
S
Andrews
Agilent Technologies, Inc., Santa Clara, California 95051, USA;
Bram
B
Herman
Agilent Technologies, Inc., Santa Clara, California 95051, USA;
Andy
A
Higgs
Agilent Technologies, Inc., Santa Clara, California 95051, USA;
Emily
E
LeProust
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
Cameron S
CS
Osborne
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada;
Jennifer A
JA
Mitchell
University College London, UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom; Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom; Okinawa Institute for Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan peter.fraser@babraham.ac.uk nicholas.luscombe@ucl.ac.uk.
Nicholas M
NM
Luscombe
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom; peter.fraser@babraham.ac.uk nicholas.luscombe@ucl.ac.uk.
Peter
P
Fraser
D000818:Animals; D001665:Binding Sites / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006657:Histones / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D014157:Transcription Factors