title: Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.
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.
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kyong-Rim
authors.initials: KR
authors.lastname: Kieffer-Kwon
authors.affiliation: The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, CT 06030, USA.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ewy
authors.initials: E
authors.lastname: Mathe
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Qian
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Myong-Hee
authors.initials: MH
authors.lastname: Sung
authors.affiliation: The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, CT 06030, USA.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Resch
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Songjoon
authors.initials: S
authors.lastname: Baek
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nathanael
authors.initials: N
authors.lastname: Pruett
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Grøntved
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Vian
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Steevenson
authors.initials: S
authors.lastname: Nelson
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Zare
authors.affiliation: Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Ofir
authors.initials: O
authors.lastname: Hakim
authors.affiliation: 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.
authors.forename: Deepak
authors.initials: D
authors.lastname: Reyon
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.affiliation: Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nakahashi
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Kovalchuk
authors.affiliation: Laboratory of Stem Cell Biology, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Zou
authors.affiliation: 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.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Joung
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.affiliation: DOE Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA 94598, USA.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wei
authors.affiliation: The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, CT 06030, USA.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
authors.affiliation: The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, CT 06030, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: 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.
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D019070:Cell Lineage; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D005821:Genetic Techniques; D051379:Mice; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics; D018085:Regulon; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D062085:RNA, Long Noncoding; D014157:Transcription Factors