Journal
GENOME RESEARCH
Volume 25, Issue 4, Pages 582-597Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.185272.114
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Funding
- Biotechnology and Biological Science Research Council, UK
- Medical Research Council, UK
- EU, FP7 Epigenesys Network of Excellence
- Canadian Institutes of Health Research
- Canada Foundation for Innovation
- Ontario Ministry of Research and Innovation
- BBSRC [BBS/E/B/000C0404, BBS/E/B/000C0405] Funding Source: UKRI
- MRC [MR/L007150/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0404, BBS/E/B/000C0405] Funding Source: researchfish
- Cancer Research UK [16358] Funding Source: researchfish
- Medical Research Council [1128090, MR/L007150/1] Funding Source: researchfish
- The Francis Crick Institute [10110, 10111] Funding Source: researchfish
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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.
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