Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals

Horvath, Attila; Daniel, Bence; Szeles, Lajos; Cuaranta-Monroy, Ixchelt; Czimmerer, Zsolt; Ozgyin, Lilla; Steiner, Laszlo; Kiss, Mate; Simandi, Zoltan; Poliska, Szilard; Giannakis, Nikolas; Raineri, Emanuele; Gut, Ivo Glynne; Nagy, Benedek; Nagy, Laszlo

Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals

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dc.contributor.author Horvath, Attila
dc.contributor.author Daniel, Bence
dc.contributor.author Szeles, Lajos
dc.contributor.author Cuaranta-Monroy, Ixchelt
dc.contributor.author Czimmerer, Zsolt
dc.contributor.author Ozgyin, Lilla
dc.contributor.author Steiner, Laszlo
dc.contributor.author Kiss, Mate
dc.contributor.author Simandi, Zoltan
dc.contributor.author Poliska, Szilard
dc.contributor.author Giannakis, Nikolas
dc.contributor.author Raineri, Emanuele
dc.contributor.author Gut, Ivo Glynne
dc.contributor.author Nagy, Benedek
dc.contributor.author Nagy, Laszlo
dc.date.accessioned 2019-07-19T08:33:48Z
dc.date.available 2019-07-19T08:33:48Z
dc.date.issued 2019
dc.description.abstract The concept of tissue-specific gene expression posits that lineage-determining transcription factors (LDTFs) determine the open chromatin profile of a cell via collaborative binding, providing molecular beacons to signal-dependent transcription factors (SDTFs). However, the guiding principles of LDTF binding, chromatin accessibility and enhancer activity have not yet been systematically evaluated. We sought to study these features of the macrophage genome by the combination of experimental (ChIP-seq, ATAC-seq and GRO-seq) and computational approaches. We show that Random Forest and Support Vector Regression machine learning methods can accurately predict chromatin accessibility using the binding patterns of the LDTF PU.1 and four other key TFs of macrophages (IRF8, JUNB, CEBPA and RUNX1). Any of these TFs alone were not sufficient to predict open chromatin, indicating that TF binding is widespread at closed or weakly opened chromatin regions. Analysis of the PU.1 cistrome revealed that two-thirds of PU.1 binding occurs at low accessible chromatin. We termed these sites labelled regulatory elements (LREs), which may represent a dormant state of a future enhancer and contribute to macrophage cellular plasticity. Collectively, our work demonstrates the existence of LREs occupied by various key TFs, regulating specific gene expression programs triggered by divergent macrophage polarizing stimuli.
dc.description.sponsorship This work has been supported by Hungarian Scientific Research Fund [NKFIH K116855, K124298, KH126885 to L.N.]; GINOP-2.3.2-15-2016-0006; GINOP-2.1.7-15-2016-01487; NIH [R01DK115924]; Campus Hungary Scholarship at Centro Nacional de Análisis Genómico (to A.H.); American Heart Association (AHA) [17POST33660450 to B.D.]. Funding for open access charge: Hungarian Scientific Research Fund [NKFIH K116855, K124298, KH126885]; NIH [R01DK115924]; GINOP 2.1.7-15-2016-01487; GINOP 2.3.2-15-2016-0006
dc.format.mimetype application/pdf
dc.identifier.citation Horvath A, Daniel B, Szeles L, Cuaranta-Monroy I, Czimmerer Z, Ozgyin L et al. Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals. Nucleic Acids Res. 2019 Apr 8;47(6):2778-92. DOI: 10.1093/nar/gkz118
dc.identifier.doi http://dx.doi.org/10.1093/nar/gkz118
dc.identifier.issn 0305-1048
dc.identifier.uri http://hdl.handle.net/10230/42071
dc.language.iso eng
dc.publisher Oxford University Press
dc.relation.ispartof Nucleic Acids Research. 2019 Apr 8;47(6):2778-92
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Genòmica
dc.subject.other Genètica
dc.subject.other Cromatina
dc.title Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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