title: Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding.
abstract: Complex regulatory landscapes control the pleiotropic transcriptional activities of developmental genes. For most genes, the number, location, and dynamics of their associated regulatory elements are unknown. In this work, we characterized the three-dimensional chromatin microarchitecture and regulatory landscape of 446 limb-associated gene loci in mouse using Capture-C, ChIP-seq, and RNA-seq in forelimb, hindlimb at three developmental stages, and midbrain. The fine mapping of chromatin interactions revealed a strong preference for functional genomic regions such as repressed or active domains. By combining chromatin marks and interaction peaks, we annotated more than 1000 putative limb enhancers and their associated genes. Moreover, the analysis of chromatin interactions revealed two regimes of chromatin folding, one producing interactions stable across tissues and stages and another one associated with tissue and/or stage-specific interactions. Whereas stable interactions associate strongly with CTCF/RAD21 binding, the intensity of variable interactions correlates with changes in underlying chromatin modifications, specifically at the viewpoint and at the interaction site. In conclusion, this comprehensive data set provides a resource for the characterization of hundreds of limb-associated regulatory landscapes and a framework to interpret the chromatin folding dynamics observed during embryogenesis.
authors.affiliation: RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Guillaume
authors.identifier: 0000-0002-0911-4907
authors.initials: G
authors.lastname: Andrey
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schöpflin
authors.affiliation: RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Ivana
authors.identifier: 0000-0001-9707-8303
authors.initials: I
authors.lastname: Jerković
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Heinrich
authors.affiliation: RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.|Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Daniel M
authors.identifier: 0000-0002-0019-3354
authors.initials: DM
authors.lastname: Ibrahim
authors.affiliation: RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Paliou
authors.affiliation: Max Planck Institute for Molecular Genetics, Sequencing Core Facility, 14195 Berlin, Germany.
authors.forename: Myriam
authors.initials: M
authors.lastname: Hochradel
authors.affiliation: Max Planck Institute for Molecular Genetics, Sequencing Core Facility, 14195 Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Timmermann
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Haas
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.affiliation: RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.|Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000818:Animals; D001665:Binding Sites; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D005121:Extremities / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D002843:Chromatin; D006657:Histones; D014157:Transcription Factors