Center for Molecular Medicine Cologne

The main focus of my lab is on dissecting the molecular basis of the structure-to-function relationship of mammalian genomes. We wish to understand how chromatin integrates different signaling stimuli to control transitions between homeostatic and deregulated gene expression programs via looping regulation – particularly how changes along the linear chromatin fibre translate into spatial networks. Deciphering the general rules that govern transcriptional homeostasis will allow us to predict how a cell might respond in disease, development, or ageing.


It is now well understood that mammalian genomes are much more than mere libraries where genetic information is stored. Due to paradigm-shifting technological advances over the last decade, we now also understand that genomes are four-dimensional entities, and should be studied in 3D space and over time in order to dissect their sequence-to-structure-to-function relationship. Our work aims at furthering our understanding of 3D genomic architecture and how this is affected by and aligned to transcriptional organization in nuclei.

3D chromatin architecture and cytokine signaling

We perform comparative studies of inflammatory (TNF) versus migratory (TGF) signaling in primary endothelial cells, in order to understand how chromatin architecture allows for their diverse signaling dynamics (the former cascade unfolds within minutes, while the latter within hours). We focus on nucleosome and transcription factor occupancy landscapes, and on differences in transcriptional dynamics between the two cascades. We already described a global “priming” mechanism, whereby thousands of regions in the genome are rendered accessible following TNF stimulation, despite the absence of bound NF-κB (the factor driving the cascade); this mechanism also facilitates forthcoming changes in 3D chromatin conformation. We are currently in the process of finding out if “priming” is a universal means for preparing the genome for ensuing transcriptional programs. More recently, we discovered how non-canonical binding of transcription factors may alter their regulatory character – and turn an activator into a facilitator of gene repression (Figure 1). As a result, to further understand the molecular basis of these dynamics we initiated a project where we apply single-nucleotide resolution sequencing of nascent RNA (using our novel approach; Melnik et al, 2016), and complement it with single-cell RNA-seq (in collaboration with Karsten Rippe, Heidelberg) and single-molecule RNA FISH. As a whole, this work is bound to uncover fundamental differences in the transcriptional organization of mammalian nuclei in response to signaling and offer novel targets in these medically-relevant pathways.

The contribution of 3D genome reorganization to the onset of cellular senescence

We have been pursuing an integrative study of cellular senescence, the intrinsic mechanism that is responsible for the prevention of tumorigenesis, but also implicated in ageing. Here, we use different primary cell types (endothelial, lung fibroblast, and mesenchymal stem cells) in an effort to identify the common molecular backbone that signals entry into senescence. The molecular events, in 3D space and over time, driving the establishment of the senescent gene expression program remain largely unexplored, but are known to involve the activation of a proinflammatory transcriptional program. To this end, we drive the three cell types into replicative senescence, perform nascent RNA-seq, and seek to identify a common regulatory backbone between all three cell type-specific transcriptional programs, with an emphasis on differentially-regulated factors that associate with chromatin. We find genes coding for regulators of chromatin conformation being suppressed, and the levels of many transcriptional repressors being induced. Next, we use the whole-genome variant of the chromosome conformation capture technology, Hi-C (see Figure 2), to identify global changes in 3D chromatin organization. We have generated and analyzed >5 billion reads from proliferating and senescent cells, leading to interaction maps of <10-kbp resolution. Using these we identified marked reorganization at the multi-Mbp domain scale, a feature underpinned by the ubiquitous increase of the nuclear volume in senescent cells. The gain and loss of spatial interactions and the shift in topological domain boundaries correlates with non-histone chromatin constituents extruded from the nucleus into extracellular space, thus contributing to the senescence-associated secretory phenotype (SASP). Our work is the first to identify a link between the SASP and the reorganization of nuclear architecture, and it points to a particular nuclear checkpoint that prepares the cell’s response in the face of senescent arrest.


Our work on the connection between 3D chromatin folding and transcriptional organization focuses on either proinflammatory signaling, or on the onset and establishment of cellular senescence. These two processes share physiological and molecular commonalities, and their dissection will offer both a chance to identify novel effectors and potential therapeutic targets, and a deeper understanding of the 3D structure-to-function code of the human genome that still remains a challenge.

  • Debes C, Papadakis A, Gronke S, Karalay O, Tain LS, Mizi A, Nakamura S, Hahn O, Weigelt C, Josipovic N, Zirkel A, Brusius I, Sofiadis K, Lamprousi M, Lu YX, Huang W, Esmaillie R, Kubacki T, Spath MR, Schermer B, Benzing T, Muller RU, Antebi A, Partridge L, Papantonis A, and Beyer A (2023). Ageing-associated changes in transcriptional elongation influence longevity. Nature 616, 814-821. doi:10.1038/s41586-023-05922-y.
  • Gabriel E, Albanna W, Pasquini G, Ramani A, Josipovic N, Mariappan A, Riparbelli MG, Callaini G, Karch CM, Goureau O, Papantonis A, Busskamp V, Schneider T, and Gopalakrishnan J (2023). Generation of iPSC-derived human forebrain organoids assembling bilateral eye primordia. Nat Protoc 18, 1893-1929. doi:10.1038/s41596-023-00814-x.
  • Papaspyropoulos A, Hazapis O, Altulea A, Polyzou A, Verginis P, Evangelou K, Fousteri M, Papantonis A, Demaria M, and Gorgoulis V (2023). Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular senescence. Aging Cell 22, e13893. doi:10.1111/acel.13893.
  • Angelopoulou A, Papaspyropoulos A, Papantonis A, and Gorgoulis VG (2022). CRISPR-Cas9-mediated induction of large chromosomal inversions in human bronchial epithelial cells. STAR Protoc3, 101257. doi:10.1016/j.xpro.2022.101257.
  • Evangelou K, Veroutis D, Paschalaki K, Foukas PG, Lagopati N, Dimitriou M, Papaspyropoulos A, Konda B, Hazapis O, Polyzou A, Havaki S, Kotsinas A, Kittas C, Tzioufas AG, de Leval L, Vassilakos D, Tsiodras S, Stripp BR, Papantonis A, Blandino G, Karakasiliotis I, Barnes PJ, and Gorgoulis VG (2022). Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis. Eur Respir J. doi:10.1183/13993003.02951-2021.
  • Franzen J, Georgomanolis T, Selich A, Kuo CC, Stoger R, Brant L, Mulabdic MS, Fernandez-Rebollo E, Grezella C, Ostrowska A, Begemann M, Nikolic M, Rath B, Ho AD, Rothe M, Schambach A, Papantonis A, and Wagner W (2021). DNA methylation changes during long-term in vitro cell culture are caused by epigenetic drift. Commun Biol4, 598. doi:10.1038/s42003-021-02116-y.
  • Gabriel E, Albanna W, Pasquini G, Ramani A, Josipovic N, Mariappan A, Schinzel F, Karch CM, Bao G, Gottardo M, Suren AA, Hescheler J, Nagel-Wolfrum K, Persico V, Rizzoli SO, Altmuller J, Riparbelli MG, Callaini G, Goureau O, Papantonis A, Busskamp V, Schneider T, and Gopalakrishnan J (2021). Human brain organoids assemble functionally integrated bilateral optic vesicles. Cell Stem Cell28, 1740-1757 e1748. doi:10.1016/j.stem.2021.07.010.
  • Goranci-Buzhala G, Mariappan A, Ricci-Vitiani L, Josipovic N, Pacioni S, Gottardo M, Ptok J, Schaal H, Callaini G, Rajalingam K, Dynlacht B, Hadian K, Papantonis A, Pallini R, and Gopalakrishnan J (2021). Cilium induction triggers differentiation of glioma stem cells. Cell Rep36, 109656. doi:10.1016/j.celrep.2021.109656.
  • Kargapolova Y, Rehimi R, Kayserili H, Bruhl J, Sofiadis K, Zirkel A, Palikyras S, Mizi A, Li Y, Yigit G, Hoischen A, Frank S, Russ N, Trautwein J, van Bon B, Gilissen C, Laugsch M, Gusmao EG, Josipovic N, Altmuller J, Nurnberg P, Langst G, Kaiser FJ, Watrin E, Brunner H, Rada-Iglesias A, Kurian L, Wollnik B, Bouazoune K, and Papantonis A (2021). Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nat Commun12, 3014. doi:10.1038/s41467-021-23327-1.
                                                                                                                                                                            • Sofiadis K, Josipovic N, Nikolic M, Kargapolova Y, Ubelmesser N, Varamogianni-Mamatsi V, Zirkel A, Papadionysiou I, Loughran G, Keane J, Michel A, Gusmao EG, Becker C, Altmuller J, Georgomanolis T, Mizi A, and Papantonis A (2021). HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence. Mol Syst Biol17, e9760. doi:10.15252/msb.20209760.
                                                                                                                                                                                                                                                                          • Zampetidis CP, Galanos P, Angelopoulou A, Zhu Y, Polyzou A, Karamitros T, Kotsinas A, Lagopati N, Mourkioti I, Mirzazadeh R, Polyzos A, Garnerone S, Mizi A, Gusmao EG, Sofiadis K, Gal Z, Larsen DH, Pefani DE, Demaria M, Tsirigos A, Crosetto N, Maya-Mendoza A, Papaspyropoulos A, Evangelou K, Bartek J, Papantonis A, and Gorgoulis VG (2021). A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization. Mol Cell81, 4907-4923 e4908. doi:10.1016/j.molcel.2021.10.017.
                                                                                                                                                                                                                                                                          • Zhang S, Ubelmesser N, Josipovic N, Forte G, Slotman JA, Chiang M, Gothe HJ, Gusmao EG, Becker C, Altmuller J, Houtsmuller AB, Roukos V, Wendt KS, Marenduzzo D, and Papantonis A (2021). RNA polymerase II is required for spatial chromatin reorganization following exit from mitosis. Sci Adv7, eabg8205. doi:10.1126/sciadv.abg8205.
                                                                                                                                                                                                                                                                          • Casa V, Moronta Gines M, Gade Gusmao E, Slotman JA, Zirkel A, Josipovic N, Oole E, van IWFJ, Houtsmuller AB, Papantonis A, and Wendt KS (2020). Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control. Genome Res 30, 515-27.
                                                                                                                                                                                                                                                                          • Mizi A, Gade Gusmao E, and Papantonis A (2020). iHi-C 2.0: A simple approach for mapping native spatial chromatin organisation from low cell numbers. Methods 170, 33-7.
                                                                                                                                                                                                                                                                          • Weiterer SS, Meier-Soelch J, Georgomanolis T, Mizi A, Beyerlein A, Weiser H, Brant L, Mayr-Buro C, Jurida L, Beuerlein K, Muller H, Weber A, Tenekeci U, Dittrich-Breiholz O, Bartkuhn M, Nist A, Stiewe T, van IWF, Riedlinger T, Schmitz ML, Papantonis A, and Kracht M (2020). Distinct IL-1alpha-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner. EMBO J 39, e101533.
                                                                                                                                                                                                                                                                          Prof. Dr. Argyris Papantonis CMMC Cologne
                                                                                                                                                                                                                                                                          Prof. Dr. Argyris Papantonis

                                                                                                                                                                                                                                                                          Institute of Pathology - University Medical Center Göttingen

                                                                                                                                                                                                                                                                          CMMC - assoc. RG 26 (former CMMC JRG Leader)

                                                                                                                                                                                                                                                                          +49 551 39 65734

                                                                                                                                                                                                                                                                          Institute of Pathology - University Medical Center Göttingen

                                                                                                                                                                                                                                                                          present adress: University Medical Center Göttingen Robert-Koch-Strasse 40

                                                                                                                                                                                                                                                                          37075 Göttingen


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                                                                                                                                                                                                                                                                          Curriculum Vitae (CV)

                                                                                                                                                                                                                                                                          Publications on PubMed

                                                                                                                                                                                                                                                                          Publications - Argyris Papantonis

                                                                                                                                                                                                                                                                          Link to PubMed

                                                                                                                                                                                                                                                                          Figure 1

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                                                                                                                                                                                                                                                                          Group Members

                                                                                                                                                                                                                                                                          Anne Zirkel (PostDoc)
                                                                                                                                                                                                                                                                          Athanasia Mizi (PostDoc)
                                                                                                                                                                                                                                                                          Yulia Kargapolova (PostDoc)
                                                                                                                                                                                                                                                                          Lilija Brant (doctoral student)
                                                                                                                                                                                                                                                                          Milos Nikolic (doctoral student)
                                                                                                                                                                                                                                                                          Konstantinos Sofiadis (doctoral student)
                                                                                                                                                                                                                                                                          Theodore Georgomanolis (technician)
                                                                                                                                                                                                                                                                          Ruiyuan Zheng (PhD student)