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 language | English (US) |
|---|---|
| Pages (from-to) | 2778-2792 |
| Number of pages | 15 |
| Journal | Nucleic acids research |
| Volume | 47 |
| Issue number | 6 |
| DOIs | |
| State | Published - Apr 8 2019 |
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ASJC Scopus subject areas
- Genetics
Cite this
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 journal › Article
}
TY - JOUR
T1 - Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals
AU - Horvath, Attila
AU - Daniel, Bence
AU - Szeles, Lajos
AU - Cuaranta-Monroy, Ixchelt
AU - Czimmerer, Zsolt
AU - Ozgyin, Lilla
AU - Steiner, Laszlo
AU - Kiss, Mate
AU - Simandi, Zoltan
AU - Poliska, Szilard
AU - Giannakis, Nikolas
AU - Raineri, Emanuele
AU - Gut, Ivo G.
AU - Nagy, Benedek
AU - Nagy, Laszlo
PY - 2019/4/8
Y1 - 2019/4/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064477457&partnerID=8YFLogxK
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U2 - 10.1093/nar/gkz118
DO - 10.1093/nar/gkz118
M3 - Article
C2 - 30799488
AN - SCOPUS:85064477457
VL - 47
SP - 2778
EP - 2792
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 1362-4962
IS - 6
ER -