@article{a1c77b1c6999441ab589b5a6b67e2498,
title = "Extensive and functional overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte derived differentiating macrophages",
abstract = "Macrophages are able to differentiate into classically polarized (M1) or alternatively polarized (M2) states upon encountering pro-inflammatory cytokines such as interferon (IFN) γ or anti-inflammatory cytokines such as interleukin (IL) -4/IL-13, respectively. Moreover, macrophages are known to regulate lipid metabolism via multiple members of the nuclear hormone receptor family, including the retinoid X receptors (RXR). It has been also documented that cytokines are able to modulate macrophage responses to lipid signals but the nature of these interactions and the underlying mechanisms of these processes especially at the level of the chromatinized genome are not well understood. Previous work from our laboratory suggested that STAT6 is a facilitator of nuclear receptor mediated transcriptional activity acting at the genome level. This prompted us to investigate genome-wide DNA binding events and the development of cistromes in human CD14+ monocyte-derived macrophages upon exposure to IL-4. We determined the impact of IL-4 on the PU.1, RXR and STAT6 cistromes within the active enhancer regions marked by H3K27-acetylation using chromatin immunoprecipitation followed by deep sequencing and integrated bioinformatics analyses. We found that about 2/3rd of the IL-4 induced STAT6 peaks co-localized with RXR peaks. These STAT6/RXR co-peaks differed at least in part from the non-overlapping RXR peaks regarding the most enriched de novo transcription factor binding motifs. Interestingly, RXR-binding was not regulated at the STAT6/RXR co-bound enhancers following IL-4 stimulation, but differential enhancer interactions were observed between the IL-4/STAT6 and RXR signaling pathways acting in a gene selective manner. Our results suggest that there is a novel, so far uncharacterized cistromic crosstalk between RXR and STAT6 that is likely to contribute to the formation of the active enhancer repertoire, transcriptome and differential signal-specific gene regulation of polarized macrophages.",
keywords = "Chromatin immunoprecipitation, Cistrome, Interleukin-4, Macrophage, Retinoid X receptor, STAT6, Trancriptome",
author = "Zsolt Czimmerer and Nagy, {Zsuzsanna S.} and Gergely Nagy and Attila Horvath and Timea Silye-Cseh and Agnes Kriston and David Jonas and Sascha Sauer and Laszlo Steiner and Bence Daniel and Deleuze, {Jean Francois} and Laszlo Nagy",
note = "Funding Information: This research was supported by the European Union and the State of Hungary , co-financed by the European Social Fund in the framework of T{\'A}MOP 4.2.4. A/2-11-1-2012-0001 {\textquoteleft}National Excellence Program{\textquoteright}. Work in the Nagy laboratory is supported by a grant from the Hungarian Scientific Research Fund ( OTKA K100196 ), and T{\'A}MOP-4.2.2/A-11/1/KONV-2012-0023 implemented through the New Hungary Development Plan co-financed by the European Social Fund and the European Regional Development Fund . Z.S.N. was the recipient of the J{\'a}nos Bolyai Research Fellowship from the Hungarian Academy of Sciences (2010–2013) and was supported by the NKTH-OTKA-EU 7KP (Marie Curie actions) Reintegration Grant . The authors would like to thank the members of the Nuclear Hormone Receptor laboratory for their help and comments. The authors would like to acknowledge the excellent skillful technical assistance of Drs. Szil{\'a}rd P{\'o}liska and Tibor Gyuris at the Clinical Genomics Center at the University of Debrecen for performing the certain parts of the ChIP sequencing. ChIP library preparation and bioinformatic analysis was performed at the Center of Clinical Genomics and Personalized Medicine of the University of Debrecen. Sequencing was performed at the Center National de Genotypage (CNG) Paris, funded by the ESGI (European Sequencing and Genotyping Infrastructure) Consortia as part of the ADIPOMACTX transnational access program. Funding Information: This research was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of T?MOP 4.2.4. A/2-11-1-2012-0001 ?National Excellence Program?. Work in the Nagy laboratory is supported by a grant from the Hungarian Scientific Research Fund (OTKA K100196), and T?MOP-4.2.2/A-11/1/KONV-2012-0023 implemented through the New Hungary Development Plan co-financed by the European Social Fund and the European Regional Development Fund. Z.S.N. was the recipient of the J?nos Bolyai Research Fellowship from the Hungarian Academy of Sciences (2010?2013) and was supported by the NKTH-OTKA-EU 7KP (Marie Curie actions) Reintegration Grant. The authors would like to thank the members of the Nuclear Hormone Receptor laboratory for their help and comments. The authors would like to acknowledge the excellent skillful technical assistance of Drs. Szil?rd P?liska and Tibor Gyuris at the Clinical Genomics Center at the University of Debrecen for performing the certain parts of the ChIP sequencing. ChIP library preparation and bioinformatic analysis was performed at the Center of Clinical Genomics and Personalized Medicine of the University of Debrecen. Sequencing was performed at the Center National de Genotypage (CNG) Paris, funded by the ESGI (European Sequencing and Genotyping Infrastructure) Consortia as part of the ADIPOMACTX transnational access program. Publisher Copyright: {\textcopyright} 2017 Elsevier B.V.",
year = "2018",
month = aug,
day = "15",
doi = "10.1016/j.mce.2017.07.034",
language = "English (US)",
volume = "471",
pages = "63--74",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",
}