title: Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations.
abstract: In multicellular organisms, transcription regulation is one of the central mechanisms modelling lineage differentiation and cell-fate determination. Transcription requires dynamic chromatin configurations between promoters and their corresponding distal regulatory elements. It is believed that their communication occurs within large discrete foci of aggregated RNA polymerases termed transcription factories in three-dimensional nuclear space. However, the dynamic nature of chromatin connectivity has not been characterized at the genome-wide level. Here, through a chromatin interaction analysis with paired-end tagging approach using an antibody that primarily recognizes the pre-initiation complexes of RNA polymerase II, we explore the transcriptional interactomes of three mouse cells of progressive lineage commitment, including pluripotent embryonic stem cells, neural stem cells and neurosphere stem/progenitor cells. Our global chromatin connectivity maps reveal approximately 40,000 long-range interactions, suggest precise enhancer-promoter associations and delineate cell-type-specific chromatin structures. Analysis of the complex regulatory repertoire shows that there are extensive colocalizations among promoters and distal-acting enhancers. Most of the enhancers associate with promoters located beyond their nearest active genes, indicating that the linear juxtaposition is not the only guiding principle driving enhancer target selection. Although promoter-enhancer interactions exhibit high cell-type specificity, promoters involved in interactions are found to be generally common and mostly active among different cells. Chromatin connectivity networks reveal that the pivotal genes of reprogramming functions are transcribed within physical proximity to each other in embryonic stem cells, linking chromatin architecture to coordinated gene expression. Our study sets the stage for the full-scale dissection of spatial and temporal genome structures and their roles in orchestrating development.
authors.affiliation: Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA.
authors.forename: Chee-Hong
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, UCSF, San Francisco, California 94158, USA.
authors.forename: Ramon Y
authors.initials: RY
authors.lastname: Birnbaum
authors.affiliation: The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, Connecticut 06030, USA.|Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biological Sciences and Biotechnology, University of Milano-Bicocca, 20126 Milano, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Favaro
authors.affiliation: Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA.
authors.forename: Chew Yee
authors.initials: CY
authors.lastname: Ngan
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lim
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Eunice
authors.initials: E
authors.lastname: Tai
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Huay Mei
authors.initials: HM
authors.lastname: Poh
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wong
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Fabianus Hendriyan
authors.initials: FH
authors.lastname: Mulawadi
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Sung
authors.affiliation: Department of Biological Sciences and Biotechnology, University of Milano-Bicocca, 20126 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Nicolis
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, UCSF, San Francisco, California 94158, USA.
authors.forename: Nadav
authors.initials: N
authors.lastname: Ahituv
authors.affiliation: The Jackson Laboratory for Genomic Medicine, and Department of Genetic and Development Biology, University of Connecticut, 400 Farmington, Connecticut 06030, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Sequencing Technology Group, Joint Genome Institute, Lawrence Berkeley National Laboratory, Walnut Creek, California 94598, USA.|Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wei
mesh_terms: D000818:Animals; D002460:Cell Line; D019070:Cell Lineage; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015027:Zebrafish / Q000235:genetics
chemical_list: D002843:Chromatin; D012319:RNA Polymerase II