The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages

Daniel, Bence; Nagy, Gergely; Hah, Nasun; Horvath, Attila; Czimmerer, Zsolt; Poliska, Szilard; Gyuris, Tibor; Keirsse, Jiri; Gysemans, Conny; Van Ginderachter, Jo A.; Balint, Balint L.; Evans, Ronald M.; Barta, Endre; Nagy, Laszlo

doi:10.1101/gad.242685.114

Cited by 97Genomics and Chromatin DynamicsChromatin Remodeling and CancerEstrogen and related hormone effects

The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages

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Daniel, Bence, Nagy, Gergely, Hah, Nasun, Horvath, Attila, Czimmerer, Zsolt, Poliska, Szilard, Gyuris, Tibor, Keirsse, Jiri +6 more·2014·Genes & Development

DOI 10.1101/gad.242685.114PMC PMC4102764

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Abstract

RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program.

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PU.1 binds to active enhancers of Trem2 and Tyrobp in ChIP-Seq experiments using mouse BV2 cells or bone marrow-derived mouse macrophages.
“Further, PU.1 binds to active enhancers of Trem2 and Tyrobp in ChIP-Seq experiments using mouse BV2 cells42 or bone marrow-derived mouse macrophages43.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [42]
The Results section on mapping cistromes in BMDMs reports PU.1 ChIP-seq peaks and active histone marks in bone marrow-derived macrophages. Our copy does not identify PU.1 binding at enhancers of Trem2 or Tyrobp, so it does not support the gene-specific part of the claim. The BV2-cell experiment is attributed to a different citation in the citing sentence. (LLM, conf=0.83)
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Self-citation
The Nuclear Receptor PPARγ Controls Progressive Macrophage Polarization as a Ligand-Insensitive Epigenomic Ratchet of Transcriptional Memory
Dániel, B., Nagy, G., Czimmerer, Z., Horváth, A., Hammers, D. W., Cuaranta‐Monroy, I., Póliska, S., Tzerpos, P., Kolostyák, Z., Hays, T. T., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.09.005 · Cited by 180 · see citing works
Self-citation
Nuclear Receptors License Phagocytosis by Trem2<sup>+</sup>Myeloid Cells in Mouse Models of Alzheimer's Disease
Savage, J. C., Jay, T., Goduni, E., Quigley, C., Mariani, M. M., Malm, T., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.4586-14.2015 · Cited by 154 · see citing works
“, 2009), and TREM2 (Daniel et al., 2014) is directly regulated by nuclear receptor agonists.”
BackgroundInfluential
A Critical Role for Estrogen-Related Receptor Signaling in Cardiac Maturation
Sakamoto, T., Matsuura, T. R., Wan, S., Ryba, D. M., Kim, J., Won, K., Lai, L., Petucci, C. J., Petrenko, N. B., Musunuru, K., et al. (2020) · Circulation Research · doi:10.1161/circresaha.119.316100 · Cited by 144 · see citing works
Hepatocyte-Macrophage Acetoacetate Shuttle Protects Against Tissue Fibrosis
Puchalska, P., Martin, S. E., Huang, X., Lengfeld, J. E., Daniel, B., Graham, M. J., Han, X., Nagy, L., Patti, G. J., & Crawford, P. A. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.10.015 · Cited by 138 · see citing works
Self-citation
Targeting innate immunity for neurodegenerative disorders of the central nervous system
Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13667 · Cited by 126 · see citing works
α‐Linolenic acid‐derived metabolites from gut lactic acid bacteria induce differentiation of anti‐inflammatory M2 macrophages through G protein‐coupled receptor 40
Ohue‐Kitano, R., Watanabe‐Yasuoka, Y., Goto, T., Kitamura, N., Park, S., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201700273r · Cited by 103 · see citing works
“PPAR-g also formed heterodimers with the nuclear receptor RXR, which is activated by 9-cis-retinoic acid and controls macrophage function (43, 44).”
Background
Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice
Skerrett, R., Pellegrino, M. P., Casali, B. T., Taraboanta, L., & Landreth, G. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.652008 · Cited by 89 · see citing works
The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands
Czimmerer, Z., Halász, L., Dániel, B., Varga, Z., Bene, K., Domokos, A., Hoeksema, M. A., Shen, Z., Berger, W. K., Cseh, T., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.004 · Cited by 91 · see citing works
“ChIP-seq—ChIP was performed with minor modifications of the previously described protocol (Daniel et al., 2014).”
BackgroundMethodSelf-citation
Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity
Penvose, A. R., Keenan, J. L., Bray, D., Ramlall, V., & Siggers, T. (2019) · Nature Communications · doi:10.1038/s41467-019-10264-3 · Cited by 87 · see citing works
Retinoid X Receptor Activation Alters the Chromatin Landscape To Commit Mesenchymal Stem Cells to the Adipose Lineage
Shoucri, B. M., Martinez, E. S., Abreo, T. J., Hung, V. T., Moosová, Z., Shioda, T., & Blumberg, B. (2017) · Endocrinology · doi:10.1210/en.2017-00348 · Cited by 78 · see citing works
“Inmacrophages,RXR is known to influence gene expression through long-range enhancers (65).”
Background
The IL-4/STAT6/PPARγ signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages
Daniel, B., Nagy, G., Horvath, A., Czimmerer, Z., Cuaranta-Monroy, I., Poliska, S., Hays, T. T., Sauer, S., Francois-Deleuze, J., & Nagy, L. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky157 · Cited by 73 · see citing works
“An intriguing piece of observation from our previous study is that the number of RXR-bound sites is not changing significantly upon ligand activation (3).”
BackgroundMethodInfluentialSelf-citation
Retinoid X Receptor Activation During Adipogenesis of Female Mesenchymal Stem Cells Programs a Dysfunctional Adipocyte
Shoucri, B. M., Hung, V. T., Chamorro-García, R., Shioda, T., & Blumberg, B. (2018) · Endocrinology · doi:10.1210/en.2018-00056 · Cited by 65 · see citing works
“vious studies report induction of RAR gene targets by rexinoids (86).”
Background
Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity
Mounier, A., Georgiev, D., Nam, K. N., Fitz, N. F., Castranio, E. L., Wolfe, C. M., Cronican, A. A., Schug, J., Lefterov, I., & Koldamova, R. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1001-15.2015 · Cited by 64 · see citing works
The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarizationPreprint
Dániel, B., Czimmerer, Z., Halász, L., Botó, P., Kolostyák, Z., Póliska, S., Berger, W. K., Tzerpos, P., Nagy, G., Horváth, A., et al. (2020) · Genes & Development · doi:10.1101/gad.343038.120 · Cited by 58 · see citing works
“ChIP was performed with minor modifications of the previously described protocol (Daniel et al. 2014a).”
MethodSelf-citation
Mechanisms of Feedback Regulation of Vitamin A Metabolism
O'Connor, C., Varshosaz, P., & Moise, A. (2022) · Nutrients · doi:10.3390/nu14061312 · Cited by 53 · see citing works
Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state
Dániel, B., Belk, J. A., Meier, S. L., Chen, A. Y., Sandor, K. D., Czimmerer, Z., Varga, Z., Bene, K., Buquicchio, F. A., Qi, Y., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.11.017 · Cited by 56 · see citing works
“41,42 In the Mgl2 locus, we detected G2/M-phase-dependent enhancer activity at the −1kb enhancer in M0 MFs, while the −14kb was silent.”
Self-citation
Pan-Cancer Analyses of the Nuclear Receptor Superfamily
Long, M. D., & Campbell, M. J. (2015) · Nuclear Receptor Research · doi:10.11131/2015/101182 · Cited by 56 · see citing works
Epigenomic PU.1-VDR crosstalk modulates vitamin D signaling
Seuter, S., Neme, A., & Carlberg, C. (2017) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2017.02.005 · Cited by 51 · see citing works
International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023
Burris, T. P., de Vera, I. M. S., Côté, I., Flaveny, C. A., Wanninayake, U. S., Chatterjee, A., Walker, J. K., Steinauer, N., Zhang, J., Coons, L. A., et al. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000436 · Cited by 53 · see citing works
Specific enhancer selection by IRF3, IRF5 and IRF9 is determined by ISRE half-sites, 5′ and 3′ flanking bases, collaborating transcription factors and the chromatin environment in a combinatorial fashion
Csumita, M., Csermely, A., Horváth, A., Nagy, G., Monori, F., Göczi, L., Orbea, H. A., Reith, W., & Széles, L. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1112 · Cited by 48 · see citing works
Self-citation
The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages
Huang, Z., Liang, N., Goñi, S., Damdimopoulos, A. E., Wang, C., Ballaire, R., Jager, J., Niskanen, H., Han, H., Jakobsson, T., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2020.12.040 · Cited by 49 · see citing works
Enhancers in the Peril lincRNA locus regulate distant but not local genes
Groff, A., Barutcu, A. R., Lewandowski, J. P., & Rinn, J. L. (2018) · Genome Biology · doi:10.1186/s13059-018-1589-8 · Cited by 26 · see citing works
“All of these factors have been significantly implicated in chromatin looping and enhancer function [29, 45, 46].”
Background
Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma
Teng, H., Xue, M., Liang, J., Wang, X., Wang, L., Wei, W., Li, C., Zhang, Z., Li, Q., Xia, R., et al. (2020) · Theranostics · doi:10.7150/thno.42559 · Cited by 44 · see citing works
“H3K27ac bigwig tracks were visualized in the UCSC Genome Browser (http://genome.ucsc.edu/cgi-bin/ hgTracks).”
BackgroundInfluential
Vitamin D Receptor and RXR in the Post‐Genomic Era
Long, M. D., Sucheston‐Campbell, L. E., & Campbell, M. J. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24847 · Cited by 43 · see citing works
“…transcriptional co-activator (Baudino et al., in press), as well as other proteins that have more recently been characterized to have coactivator function (e.g., CCND3) have been associated with VDR function (Cenciarelli et al., 1999; Lazaro et al., 2002; Despouy et al., 2003; Sarruf et al., 2005).”
Background
The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p
Czimmerer, Z., Varga, T., Kiss, M., Vázquez, C., Doan‐Xuan, Q. M., Rückerl, D., Tattikota, S. G., Yan, X., Nagy, Z. S., Dániel, B., et al. (2016) · Genome Medicine · doi:10.1186/s13073-016-0315-y · Cited by 40 · see citing works
“For this reason we analyzed publicly available GRO-seq data from unstimulated and ChIP-seq datasets from both IL-4-stimulated and unstimulated mouse macrophages [65, 66].”
MethodSelf-citation
RXR heterodimers orchestrate transcriptional control of neurogenesis and cell fate specification
Simándi, Z., Horváth, A., Cuaranta‐Monroy, I., Sauer, S., Deleuze, J., & Nagy, L. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.07.033 · Cited by 37 · see citing works
Self-citation
PETModule: a motif module based approach for enhancer target gene prediction
Zhao, C., Li, X.-M., & Hu, H.-Y. (2016) · Scientific Reports · doi:10.1038/srep30043 · Cited by 35 · see citing works
“We also downloaded 387 validated ETG pairs by 3C experiments in mouse macrophage 36 .”
Bexarotene promotes microglia/macrophages - Specific brain - Derived Neurotrophic factor expression and axon sprouting after traumatic brain injury
He, J., Huang, Y., Liu, H., Sun, X., Wu, J., Zhang, Z., Liu, L., Zhou, C., Jiang, S., Huang, Z., et al. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113462 · Cited by 36 · see citing works
RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment
Lefterov, I. M., Schug, J., Mounier, A., Nam, K. N., Fitz, N. F., & Koldamova, R. P. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.05.019 · Cited by 36 · see citing works
“In fact, the precise molecular mechanisms used by RXR to interact with the genome and to regulate gene expression are still not known (Daniel et al., 2014).”
Background
Transcriptional repression in macrophages—basic mechanisms and alterations in metabolic inflammatory diseases
Treuter, E., Fan, R., Huang, Z., Jakobsson, T., & Venteclef, N. (2017) · FEBS Letters · doi:10.1002/1873-3468.12850 · Cited by 34 · see citing works
TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor
Ferrara, S. J., Chaudhary, P., DeBell, M. J., Marracci, G., Miller, H. I., Calkins, E., Pocius, E., Napier, B. A., Emery, B., BOURDETTE, D. N., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.07.014 · Cited by 32 · see citing works
Motif oriented high-resolution analysis of ChIP-seq data reveals the topological order of CTCF and cohesin proteins on DNA
Nagy, G., Czipa, E., Steiner, L., Nagy, T., Pongor, S., Nagy, L., & Barta, E. (2016) · BMC Genomics · doi:10.1186/s12864-016-2940-7 · Cited by 27 · see citing works
“Earlier, we assigned the RXR-activated enhancers to induced genes in bone marrow derived macrophages through the use of regions bordered by active insulators that were bound both by CTCF and RAD21 [26].”
BackgroundSelf-citation
SWI/SNF-dependent genes are defined by their chromatin landscape
Basurto-Cayuela, L., Guerrero-Martinez, J. A., Gómez-Marín, E., Sánchez-Escabias, E., Escaño‐Maestre, M., Ceballos-Chávez, M., & Reyes, J. C. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113855 · Cited by 30 · see citing works
Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism
Kiss, M., Czimmerer, Z., Nagy, G., Bieniasz-Krzywiec, P., Ehling, M., Pap, A., Póliska, S., Botó, P., Tzerpos, P., Horváth, A., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700785114 · Cited by 29 · see citing works
“RXR ’ s activity can be assessed by examining the regulation of the target genes of its A LG268 (min) 30 60 120 LG268 (min) 30 60 120 heterodimeric partners, since specific target genes for homodimeric RXR signaling have not been unequivocally established.”
InfluentialSelf-citation
Spotlight on the transglutaminase 2 gene: a focus on genomic and transcriptional aspects
Bianchi, N., Beninati, S., & Bergamini, C. M. (2018) · Biochemical Journal · doi:10.1042/bcj20170601 · Cited by 27 · see citing works
Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity
Long, M. D., van den Berg, P. R., Russell, J. L., Singh, P. K., Battaglia, S., & Campbell, M. J. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv642 · Cited by 25 · see citing works
Epigenomic regulation of macrophage polarization: Where do the nuclear receptors belong?
Czimmerer, Z., & Nagy, L. (2023) · Immunological Reviews · doi:10.1111/imr.13209 · Cited by 24 · see citing works
Self-citation
Extensive and functional overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte derived differentiating macrophages
Czimmerer, Z., Nagy, Z. S., Nagy, G., Horváth, A., Cseh, T., Kriston, A., Jonas, D., Sauer, S., Steiner, L., Dániel, B., et al. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.07.034 · Cited by 23 · see citing works
Self-citation
Insights into interplay between rexinoid signaling and myogenic regulatory factor-associated chromatin state in myogenic differentiation
Hamed, M., Khilji, S., Dixon, K., Blais, A., Ioshikhes, I. P., Chen, J., & Li, Q. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx800 · Cited by 21 · see citing works
“Following ChIP, purified DNA was amplified in triplicate real-time PCR reactions with locus-specific primers described previously (16,28,29,42) or in Supplementary Table S2.”
Method
APOEε4 and risk of Alzheimer’s disease – time to move forward
Lefterov, I. M., Fitz, N. F., Lü, Y., & Koldamova, R. P. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1195724 · Cited by 23 · see citing works
Novel mediators regulating angiogenesis in diabetic foot ulcer healing
Rai, V., Le, H., & Agrawal, D. K. (2023) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2023-0193 · Cited by 21 · see citing works
Current understanding on TREM-2 molecular biology and physiopathological functions
Bharadwaj, S., Groza, Y., Mierzwicka, J. M., & Malý, P. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112042 · Cited by 22 · see citing works
Sleep, neuronal hyperexcitability, inflammation and neurodegeneration: Does early chronic short sleep trigger and is it the key to overcoming Alzheimer’s disease?
Ahnaou, A., & Drinkenburg, W. H. I. M. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.06.039 · Cited by 23 · see citing works
Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects
Wan, L., Li, W., Meng, Y., Hou, Y., Chen, M., & Xu, B. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.849451 · Cited by 20 · see citing works
“Conversely, eRNAs coordinate cohesinCTCF loop formation to promote chromosome cyclisation (13, 79, 103, 104).”
BackgroundMethod
Lineage-determining transcription factor-driven promoters regulate cell type-specific macrophage gene expression
Nagy, G., Bojcsuk, D., Tzerpos, P., Cseh, T., & Nagy, L. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae088 · Cited by 17 · see citing works
Self-citation
Diet-dependent natriuretic peptide receptor C expression in adipose tissue is mediated by PPARγ via long-range distal enhancers
Shi, F., Simándi, Z., Nagy, L., & Collins, S. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100941 · Cited by 15 · see citing works
“The TK promoter and the Angptl4 enhancer were used as negative and positive controls, respectively, as described in a previous report (27).”
MethodSelf-citation
Bexarotene attenuates early brain injury via inhibiting micoglia activation through PPARγ after experimental subarachnoid hemorrhage
Tu, L., Yang, X., Zhang, Q., Wang, Q., Tian, T., Liu, D., Qu, X., & Tian, J. (2018) · Neurological Research · doi:10.1080/01616412.2018.1463900 · Cited by 16 · see citing works
Role of triggering receptor expressed on myeloid cells 2 (TREM2) in neurodegenerative dementias
Shafi, S., Singh, A., Ibrahim, A. M., Alhajri, N., Izneid, T. A., & Pottoo, F. H. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15215 · Cited by 15 · see citing works
“1 and the RXR agonist, bexarotene, are both examples of transcription factors that are known to enhance the expression of TREM2 (Daniel et al., 2014; Satoh et al., 2014).”
Background
Genomewide effects of peroxisome proliferator‐activated receptor gamma in macrophages and dendritic cells – revealing complexity through systems biology
Cuaranta‐Monroy, I., Kiss, M., Simándi, Z., & Nagy, L. (2015) · European Journal of Clinical Investigation · doi:10.1111/eci.12491 · Cited by 15 · see citing works
Self-citation
The transcriptional control of the VEGFA-VEGFR1 (FLT1) axis in alternatively polarized murine and human macrophages
Domokos, A., Varga, Z., Jambrovics, K., Caballero-Sánchez, N., Szabó, E. V., Nagy, G., Scholtz, B., Halász, L., Váradi, E., Bene, K., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1168635 · Cited by 14 · see citing works
“such as hypoxia, lipopolysaccharide, nuclear receptor agonists and lactic acid can robustly enhance their VEGFA-producing capacity resulting in the development of proangiogenic macrophage phenotype (14, 15, 37, 57, 58).”
BackgroundInfluentialSelf-citation
Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
Plens-Gałąska, M., Szeląg, M., Collado, A., Marqués, P., Vallejo, S., Ramos-González, M., Wesoły, J., Sanz, M., Peiró, C., & Bluyssen, H. A. R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02141 · Cited by 14 · see citing works
Retinoid X Receptor-selective Signaling in the Regulation of Akt/Protein Kinase B Isoform-specific Expression
AlSudais, H., Aabed, K., Nicola, W., Dixon, K., Chen, J., & Li, Q. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.692707 · Cited by 14 · see citing works
“In addition, it has been shown that H4K5/8 acetylation, but not H3K27 acetylation, increases on putative RXR-bound enhancers upon RXR ligand activation (40).”
BackgroundResultInfluential
Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals
Horváth, A., Dániel, B., Széles, L., Cuaranta‐Monroy, I., Czimmerer, Z., Ozgyin, L., Steiner, L., Kiss, M., Simándi, Z., Póliska, S., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz118 · Cited by 13 · see citing works
Self-citation
Sterol-regulated transmembrane protein TMEM86a couples LXR signaling to regulation of lysoplasmalogens in macrophages
van Wouw, S. A. E., van den Berg, M., Ouraoui, M. E., Meurs, A., Kingma, J., Ottenhoff, R., Loix, M., Hoeksema, M. A., Prange, K. H. M., Pasterkamp, G., et al. (2022) · Journal of Lipid Research · doi:10.1016/j.jlr.2022.100325 · Cited by 13 · see citing works
“Additionally, we also incorporated ChIP-seq data from Daniel et al. (48) . describing the genome-wide localization analyses of RXR in BMDM treated with GW (sequence read archive accession SRR1514119).”
Method
Transcriptional control of transglutaminase 2 expression in mouse apoptotic thymocytes
Sándor, K., Dániel, B., Kiss, B., Kovács, F., & Szondy, Z. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2016.05.011 · Cited by 13 · see citing works
Involvement of non-coding RNAs and transcription factors in the induction of Transglutaminase isoforms by ATRA
Franzese, O., Minotti, L., Aguiari, G., Corrà, F., Cervellati, C., Ferrari, C., Volinia, S., Bergamini, C. M., & Bianchi, N. (2019) · Amino Acids · doi:10.1007/s00726-019-02766-7 · Cited by 11 · see citing works
Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches
Czimmerer, Z., Horváth, A., Dániel, B., Nagy, G., Cuaranta‐Monroy, I., Kiss, M., Kolostyák, Z., Póliska, S., Steiner, L., Giannakis, N., et al. (2017) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2017.11.003 · Cited by 9 · see citing works
“(2x4) LPS-treated time-course GRO-seq samples according to our previous work [46].”
MethodInfluentialSelf-citation
Long non-coding RNA SeT and miR-155 regulate the Tnfα gene allelic expression profile
Stathopoulou, C., Kapsetaki, M., Stratigi, K., & Spilianakis, C. G. (2017) · PLoS ONE · doi:10.1371/journal.pone.0184788 · Cited by 9 · see citing works
EGR2 is an epigenomic regulator of phagocytosis and antifungal immunity in alveolar macrophages
Kolostyák, Z., Bojcsuk, D., Baksa, V., Szigeti, Z. M., Bene, K., Czimmerer, Z., Botó, P., Fadel, L., Póliska, S., Halász, L., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.164009 · Cited by 8 · see citing works
“By measuring the enhancer RNA (eRNA) level as surrogates of enhancer activity [17, 18] of three overlapping (E12, E13, and E23) and three AM-specific (E14.”
BackgroundSelf-citation
Role of TREM2 in neuroinflammation regulation: mechanisms, disease associations, and therapeutic translation advances
Liao, Y., Mu, G., Deng, S., Lu, B. F., & Zheng, M. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07604-x · Cited by 8 · see citing works
“Small molecules [82–93] and protein receptors [94–97] also exert regulatory effects on TREM2, though the mechanisms remain undefined.”
A long non-coding RNA inside the type 2 transglutaminase gene tightly correlates with the expression of its transcriptional variants
Minotti, L., Baldassari, F., Galasso, M., Volinia, S., Bergamini, C. M., & Bianchi, N. (2018) · Amino Acids · doi:10.1007/s00726-017-2528-9 · Cited by 8 · see citing works
“The enhancer activity of eRNAs involved the formation in TGM2 promoter of complexes with transcription factors and proteins having chromatin structural looping functions (Daniel et al. 2014).”
BackgroundInfluential
Regulation of immune signal integration and memory by inflammation-induced chromosome conformation
Dániel, B., Chen, A. Y., Sandor, K. D., Zhang, W., Miao, Z., Yost, K. E., Lareau, C. A., Chang, H. Y., & Satpathy, A. T. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2600693123 · Cited by 7 · see citing works
“This rapid transcrip tional response is the consequence of a primed epigenetic state, in which accessible, gene - distant regulatory elements (enhancers) are brought near gene promoters to induce gene expression (9–13).”
Global Run-on Sequencing (GRO-Seq)
Tzerpos, P., Dániel, B., & Nagy, L. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1597-3_2 · Cited by 7 · see citing works
Self-citation
Unorthodox Transcriptional Mechanisms of Lipid-Sensing Nuclear Receptors in Macrophages: Are We Opening a New Chapter?
Czimmerer, Z., Halász, L., & Nagy, L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.609099 · Cited by 7 · see citing works
“It has been shown that RXR ligand activation leads to elevated VEGFa production, enhanced leukocyte migration, and altered inflammatory response and metabolism (57, 58).”
BackgroundMethodInfluentialSelf-citation
Unraveling the Hierarchy of cis and trans Factors That Determine the DNA Binding by Peroxisome Proliferator-Activated Receptor γ
Nagy, G., Dániel, B., Cuaranta‐Monroy, I., & Nagy, L. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00547-19 · Cited by 6 · see citing works
“Isolation and differentiation of bone marrow cells derived from 3-month-old male C57BL/6 mice were completed as described previously (30, 43).”
BackgroundMethodSelf-citation
Prediction and Validation of Gene Regulatory Elements Activated During Retinoic Acid Induced Embryonic Stem Cell Differentiation
Simándi, Z., Horváth, A., Nagy, P., & Nagy, L. (2016) · Journal of Visualized Experiments · doi:10.3791/53978 · Cited by 5 · see citing works
Self-citation
The transcription factor BACH1 couples chromatin priming and repression to enable macrophage plasticity and adaptation
Tzerpos, P., Bojcsuk, D., Bene, K., Caballero-Sánchez, N., Parteka-Tojek, Z., Banecki, K. H., Korsak, S., Pritchett, S. M., Patsalos, A., Oleksak, D., et al. (2026) · Immunity · doi:10.1016/j.immuni.2026.06.022 · Cited by 4 · see citing works
Self-citation
Retinoid-X-Receptor as a Mediator of Poststroke Recovery by Reversing Age-Associated Phenotypes of Microglia/Hematogenous Macrophages
Ting, S., Zhao, X., Sun, G., Ricote, M., & Aronowski, J. A. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.0248-25.2025 · Cited by 4 · see citing works
Feedback regulation of retinaldehyde reductase DHRS3 , a critical determinant of retinoic acid homeostasis
Varshosaz, P., O'Connor, C., & Moise, A. R. (2024) · FEBS Letters · doi:10.1002/1873-3468.15038 · Cited by 4 · see citing works
Gene expression profiling discerns molecular pathways elicited by ligand signaling to enhance the specification of embryonic stem cells into skeletal muscle lineage
Dixon, K., Chen, J., & Li, Q. (2017) · Cell & Bioscience · doi:10.1186/s13578-017-0150-x · Cited by 4 · see citing works
“Although the precise role of RXR in myogenic differentiation remains to be determined, advances in next generation sequencing have allowed the mapping of RXRα binding sites genomewide in other cellular systems [34, 42, 43].”
Background
Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis
Campanelli, R., Fois, G., Catarsi, P., Poletto, V., Villani, L., Erba, B. G., Maddaluno, L., Jemos, B., Salmoiraghi, S., Guglielmelli, P., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0156990 · Cited by 4 · see citing works
“1), whose link with the V617F Jak2 mutation has been described [36], has also been associated, in a chick yolk-sac experimental model system, with an angiogenic activity of macrophages that is mediated by the RXR family of nuclear receptors [37].”
Background
Modulation of Rxrα Expression in Mononuclear Phagocytes Impacts on Cardiac Remodeling after Ischemia-Reperfusion Injury
Räuber, S. J., Fischer, M., Messerer, D., Wimmler, V., Kumaraswami, K., Todica, A. S., Lorenz, M., Titova, A., Schulz, C., & Weinberger, T. (2022) · Biomedicines · doi:10.3390/biomedicines10061274 · Cited by 3 · see citing works
“Different studies on the pathophysiological role of RXRs have been performed so far [10,11,14,17,19,20]; however, the function of RXRα in mononuclear phagocytes after MI remains elusive to date.”
BackgroundInfluential
A Comprehensive Toolbox to Analyze Enhancer–Promoter Functions
Giaimo, B. D., Friedrich, T., & Borggrefe, T. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1597-3_1 · Cited by 3 · see citing works
An intriguing characteristic of enhancer-promoter interactions
Talukder, A., Hu, H., & Li, X. (2021) · BMC Genomics · doi:10.1186/s12864-021-07440-5 · Cited by 3 · see citing works
Retinoid-X receptor action and disruption in development
Mengeling, B. J., & Furlow, J. D. (2026) · Developmental Biology · doi:10.1016/j.ydbio.2026.03.003 · Cited by 2 · see citing works
“For example, addition of RXR agonists increases the ChIP-seq signal at binding sites bound in the absence of RXR agonist (Daniel et al., 2014), rather than increasing or changing the repertoire of sites bound by the heterodimer.”
eaQTLdb : An atlas of enhancer activity quantitative trait loci across cancer types
Yuan, J., Tong, Y., Liu, X., Li, M. J., Zhang, Q., & Yang, Y. (2023) · International Journal of Cancer · doi:10.1002/ijc.34481 · Cited by 2 · see citing works
“10 Through enhancer-promoter interactions, eRNAs derived from VEGFA and TGM2 enhancers were found to maintain macrophage activity through enhancer interactions, 11 whereas the LINC00987/A2M axis was found to be significantly associated with immune cell infiltration in lung cancer.”
Background
A Common Haplotype Lowers PU.1 Expression in Myeloid Cells and Delays Onset of Alzheimer's Disease
Huang, K.-L., Marcora, E., Pimenova, A. A., Di Narzo, A. F., Kapoor, M., Jin, S. C., Harari, O., Bertelsen, S., Fairfax, B. P., Czajkowski, J., et al. (2017) · doi:10.1101/110957 · Cited by 6 · see citing works
BACH1 orchestrates macrophage state transitions to coordinate regenerative inflammation
Caballero-Sánchez, N., Tzerpos, P., Bene, K., Halász, L., Bojcsuk, D., Nagy, G., Ali, M. A., Cseh, T., Póliska, S., Borok, M. J., et al. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkag101 · Cited by 1 · see citing works
Self-citation
CpG content contributes to tissue-resident macrophage enhancer selection
Bojcsuk, D., Varga, Z., Kolostyák, Z., Tzerpos, P., Caballero-Sánchez, N., Cseh, T., Patsalos, A., Czimmerer, Z., Nagy, L., & Nagy, G. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag824 · Cited by 1 · see citing works
“Cell isolation and differentiation were performed as described earlier [ 4 ].”
Self-citation
Liver X Receptors and Inflammatory-Induced C/EBPβ Selectively Cooperate to Control CD38 Transcription
Glaría, E., Martínez, P. R., Font-Díaz, J., de la Rosa, J. V., Castrillo, A., Crawshaw, D. J., Vidal-Taboada, J. M., Saura, J., Matalonga, J., Chini, E. N., et al. (2024) · Journal of Innate Immunity · doi:10.1159/000543274 · Cited by 1 · see citing works
“…data for CEBP β were obtained from the accession number GSE109965 [46], using BMDMs from C57BL/6J mice, either left untreated or stimulated with Kdo2-Lipid A for 1 h. ChIP-Seq data for RXR correspond to BMDMs, either control or treated with GW3965 for 1 h, from the accession number SRP019970 [47].”
Association of VEGF promoter polymorphisms with gastrointestinal tract cancer risk and therapy response: a systematic review
Mahajan, D., Sambyal, V., & Guleria, K. (2025) · Egyptian Journal of Medical Human Genetics · doi:10.1186/s43042-025-00634-6 · Cited by 1 · see citing works
“The activation of RXR-controlled enhancers in VEGF by RXR was reported to effect tumour progression by inducing proangiogenic transcription [182].”
Vitamin D and Chromatin
Carlberg, C. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809965-0.00013-6
“1 [43], ER and FOXA1 [44], GR and FOXA1 [45], VDR and RUNX2 as well as for VDR and CEBPβ [37].”
Background
Computational Study of Target Gene Interactions - Enhancers and microRNAs
Talukder, A. (2021) · Journal of International Crisis and Risk Communication Research
Vitamin D, chromatin, and epigenetics
Carlberg, C. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-91386-7.00016-7
Additional file 1 of An intriguing characteristic of enhancer-promoter interactions
Talukder, A., Hu, H., & Li, X. (2021) · Figshare · doi:10.6084/m9.figshare.14184000
Genome-wide chromatin profiling reveals a nonlimiting role for RXR in macrophage-like cells stimulated with multiple nuclear receptor agonists
Mianesaz, H., Göczi, L., Bojcsuk, D., Ghalamkari, S., Fadel, L., Póliska, S., Penyige, A., Nagy, L., Nagy, G., Vámosi, G., et al. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.111486
“Cells were then stimulated with 1:1 DMSO-ethanol (vehicle) or agonists for RAR α (100 nM AM580, BioVision), VDR (100 nM calcitriol or 1 α ,25-dihydroxyvitamin D3 (1,25-vitD), Sigma-Aldrich), PPAR δ (100 nM GW501516 (GW1516), Sigma-Aldrich), PPAR γ (1 μ M RSG, Cayman chemical), LXR (1 μ M GW3965, Sigma-Aldrich), TR (10…”
InfluentialSelf-citation
Synergistic interaction between the macrophage polarizing signals IL-4 and IFNγ is controlled by the STAT6/STAT1/IRF1 axis
Varga, Z., Poscher, A., Váradi, E., Cinege, G., Izsán, A., Erdős, E., Benyhe-Kis, B., Tihanyi, A. Z., Tzerpos, P., Bene, K., et al. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag825
“Bone marrow isolation and differentiation were completed as described earlier [ 24 , 25 ].”
Self-citation

Investigation of the function of Retionid X Receptor in mouse bone marrow-derived macrophages using novel genomic approaches
Dániel, B. (2014) · University of Debrecen Electronic Archive (University of Debrecen)
The IL-4/STAT6/PPARγ signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages
Daniel, B., Nagy, G., Horvath, A., Czimmerer, Z., Cuaranta-Monroy, I., Poliska, S., Hays, T. T., Sauer, S., Francois-Deleuze, J., & Nagy, L. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky157 · Cited by 73 · see citing works
Self-citation
Global analysis of RXR-regulated genes in macrophages reveals a gene network potentially involved in promoting angiogenesis and metastasis
Kiss, M. (2015) · University of Debrecen Electronic Archive (University of Debrecen)
Genome-wide profiling of transcribed enhancers during macrophage activationPreprint
Denisenko, E., Guler, R., Mhlanga, M. M., Suzuki, H., Brombacher, F., & Schmeier, S. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/163519
Transcription of the Vascular Endothelial Growth Factor Gene in Macrophages Is Regulated by Liver X Receptors
Walczak, R., Joseph, S. B., Laffitte, B. A., Castrillo, A., Pei, L., & Tontonoz, P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310587200 · Cited by 71 · see citing works

Authors: Daniel, B., Nagy, G., Hah, N., Horvath, A., Czimmerer, Z., Poliska, S., Gyuris, T., Keirsse, J., Gysemans, C., Van Ginderachter, J. A., Balint, B. L., Evans, R. M., Barta, E., & Nagy, L.
Affiliations: University of Debrecen (HU)
Salk Institute for Biological Studies (US)
Vrije Universiteit Brussel (BE)
KU Leuven (BE)
Corresponding author: Nagy, Gergely
ORCID: Nagy, Gergely
Hah, Nasun
Czimmerer, Zsolt
Keirsse, Jiri
Gysemans, Conny
Evans, Ronald M.
Barta, Endre
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2014-07-15
Volume: 28
Issue: 14
Pages: 1562-1577
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.242685.114
PMC: PMC4102764
OpenAlex: W2101093278
Cited by: 97
References: 57
Citations by year: 2026: 7 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 7 · 2019: 4 · 2018: 11 · 2017: 15 · 2016: 9 · 2015: 10 · 2014: 1
Type: posted content
Language: en
Open access: hybrid
doi.org
Licence: cc-by
Locations: Genes & Development (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
Lirias (KU Leuven) (submittedVersion, cc-by)
University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, cc-by)
HighWire Press Open Archive (submittedVersion)
VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders: Howard Hughes Medical Institute (DK057978)
March of Dimes Foundation (DK057978, HL088093)
Entertainment Industry Foundation
Northwestern University
Hungarian Scientific Research Fund (A/2-11-1-2012-0001, OTKA K100196, K100196, -2012-0001)
KU Leuven
Vlaamse Liga Tegen Kanker
Debreceni Egyetem (-2012-0001)
National Institutes of Health (-0001, DK057978, HL088093)
Stand Up To Cancer (SU2C-AACR-DT0509)
National Heart, Lung, and Blood Institute (R01HL105278, HL-088093, P01HL088093)
National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK057978, R01DK057978)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords: retinoid X receptor, macrophages, active enhancers, enhancer RNA, PU.1, P300, CTCF, cohesin, 3D genome organization, long-range enhancer-promoter interactions, angiogenesis, VEGF-A, transcriptional regulation
MeSH terms: Animals, Cells, Cultured, Enhancer Elements, Genetic, Histones, Ligands, Macrophages, Organic Chemicals, RNA, Transcription, Genetic, Gene Expression Regulation, Developmental, Neovascularization, Physiologic, Retinoid X Receptors, Mice

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The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages

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