title: Epigenomics-Based Identification of Major Cell Identity Regulators within Heterogeneous Cell Populations.
abstract: Cellular heterogeneity within embryonic and adult tissues is involved in multiple biological and pathological processes. Here, we present a simple epigenomic strategy that allows the functional dissection of cellular heterogeneity. By integrating H3K27me3 chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data, we demonstrate that the presence of broad H3K27me3 domains at transcriptionally active genes reflects the heterogeneous expression of major cell identity regulators. Using dorsoventral patterning of the spinal neural tube as a model, the proposed approach successfully identifies the majority of previously known dorsoventral patterning transcription factors with high sensitivity and precision. Moreover, poorly characterized patterning regulators can be similarly predicted, as shown for ZNF488, which confers p1/p2 neural progenitor identity. Finally, we show that, as our strategy is based on universal chromatin features, it can be used to functionally dissect cellular heterogeneity within various organisms and tissues, thus illustrating its potential applicability to a broad range of biological and pathological contexts.
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Rehimi
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Milos
authors.initials: M
authors.lastname: Nikolic
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Cruz-Molina
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Tebartz
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center and Systems Biology of Ageing Cologne, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Mahabir
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center and Systems Biology of Ageing Cologne, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany. Electronic address: mathieu.clement-ziza@uni-koeln.de.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Clément-Ziza
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center and Systems Biology of Ageing Cologne, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany. Electronic address: aradaigl@uni-koeln.de.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Rada-Iglesias
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation / Q000379:methods; D057890:Epigenomics; D018507:Gene Expression Regulation, Developmental; D018740:Genetic Heterogeneity; D016678:Genome; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D051379:Mice; D054259:Neural Tube / Q000254:growth & development / Q000378:metabolism; D017423:Sequence Analysis, RNA / Q000379:methods; D013131:Spine / Q000254:growth & development / Q000378:metabolism
chemical_list: D002843:Chromatin; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse
keywords: H3K27me3; dorsoventral; epigenomic; gene expression; heterogeneity; patterning; spinal neutral tube