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Cell. 2013 Dec 19;155(7):1507-20. doi: 10.1016/j.cell.2013.11.039.

Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

Author information

1
Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
2
The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, CT 06030, USA.
3
Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
4
Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
5
Bar-Ilan University, Ramat-Gan 5290002, Israel.
6
Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115 USA.
7
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
8
Laboratory of Stem Cell Biology, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
9
DOE Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA 94598, USA.
10
Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA; Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rafael.casellas@nih.gov.

Abstract

A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, we here combined DNaseI hypersensitivity, ChIP-seq, and ChIA-PET technologies to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. We confirm that enhancer usage varies widely across tissues. Unexpectedly, we find that this feature extends to broadly transcribed genes, including Myc and Pim1 cell-cycle regulators, which associate with an entirely different set of enhancers in ES and B cells. By means of high-resolution CpG methylomes, genome editing, and digital footprinting, we show that these enhancers recruit lineage-determining factors. Furthermore, we demonstrate that the turning on and off of enhancers during development correlates with promoter activity. We propose that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner.

PMID:
24360274
PMCID:
PMC3905448
DOI:
10.1016/j.cell.2013.11.039
[Indexed for MEDLINE]
Free PMC Article

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