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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2778-2792
Number of pages15
JournalNucleic acids research
Volume47
Issue number6
DOIs
StatePublished - Apr 8 2019

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Chromatin
Macrophages
Genome
Transcription Factors
Gene Expression

ASJC Scopus subject areas

  • Genetics

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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 G.; Nagy, Benedek; Nagy, Laszlo.

In: Nucleic acids research, Vol. 47, No. 6, 08.04.2019, p. 2778-2792.

Research output: Contribution to journalArticle

Horvath, A, Daniel, B, Szeles, L, Cuaranta-Monroy, I, Czimmerer, Z, Ozgyin, L, Steiner, L, Kiss, M, Simandi, Z, Poliska, S, Giannakis, N, Raineri, E, Gut, IG, Nagy, B & Nagy, L 2019, 'Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals', Nucleic acids research, vol. 47, no. 6, pp. 2778-2792. https://doi.org/10.1093/nar/gkz118
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 G. ; Nagy, Benedek ; Nagy, Laszlo. / Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals. In: Nucleic acids research. 2019 ; Vol. 47, No. 6. pp. 2778-2792.
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