{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:19:24Z","timestamp":1788520764386,"version":"build-2803163510"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Three-dimensional long-range contacts between enhancers and promoters are thought to be largely determined by loop extrusion driven by the cohesin complex and insulator factors. However, recent evidence also suggests a role for noncoding RNAs, such as enhancer-associated RNAs and promoter upstream transcripts, in shaping enhancer-promoter connectivity. While the nuclear RNA exosome, together with targeting complexes, poly(A) tail exosome targeting connection and nuclear exosome targeting complex, controls the decay of noncoding RNAs, it remains unclear whether these complexes regulate three-dimensional chromatin contacts. Chromatin recruitment maps of the nuclear exosome targeting complex subunit ZCCHC8, the poly(A) tail exosome targeting connection subunit ZFC3H1, and the RNA helicase MTR4 in human cells reveal that these factors associate with sites of enhancer\u2013promoter interactions. Depletion of these factors leads to the accumulation of ncRNAs, notably enhancer-associated RNAs and promoter upstream transcripts, and increases cohesin occupancy at these sites. Chromatin conformation capture analysis reveals that MTR4 modulates long-range enhancer-promoter contacts. Upon loss of MTR4, enhancer-promoter contacts increase while intraloop contacts decrease, suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of noncoding RNAs by nuclear RNA exosome targeting complexes that is consistent with a role for RNA in genome folding.<\/jats:p>","DOI":"10.1038\/s41467-026-76396-5","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T17:24:40Z","timestamp":1786037080000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nuclear exosome targeting complexes modulate cohesin binding and enhancer-promoter interactions in 3D"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8773-5127","authenticated-orcid":false,"given":"Charbel","family":"Akkawi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Heurteau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0748-6923","authenticated-orcid":false,"given":"Xavier","family":"Contreras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Helsmoortel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Schaak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Bossuyt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Fosseprez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7999-7450","authenticated-orcid":false,"given":"David","family":"D\u00e9pierre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Cuvier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6645-0686","authenticated-orcid":false,"given":"Rosemary","family":"Kiernan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"76396_CR1","doi-asserted-by":"crossref","unstructured":"Rowley, M. J. & Corces, V. G. Organizational principles of 3D genome architecture. Nat. Rev. Genet. 19, 789\u2013800 (2018).","DOI":"10.1038\/s41576-018-0060-8"},{"key":"76396_CR2","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nrg.2016.112","volume":"17","author":"B Bonev","year":"2016","unstructured":"Bonev, B. & Cavalli, G. Organization and function of the 3D genome. Nat. Rev. Genet. 17, 661\u2013678 (2016).","journal-title":"Nat. Rev. Genet."},{"key":"76396_CR3","doi-asserted-by":"crossref","unstructured":"Ea, V., Baudement, M. O., Lesne, A. & Forne, T. Contribution of topological domains and loop formation to 3D chromatin organization. Genes. (Basel) 6, 734\u2013750 (2015).","DOI":"10.3390\/genes6030734"},{"key":"76396_CR4","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1146\/annurev-genom-083115-022339","volume":"17","author":"M Merkenschlager","year":"2016","unstructured":"Merkenschlager, M. & Nora, E. P. CTCF and cohesin in genome folding and transcriptional gene regulation. Annu. Rev. Genomics Hum. Genet. 17, 17\u201343 (2016).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"76396_CR5","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ceb.2016.01.009","volume":"40","author":"MJ Rowley","year":"2016","unstructured":"Rowley, M. J. & Corces, V. G. The three-dimensional genome: principles and roles of long-distance interactions. Curr. Opin. Cell Biol. 40, 8\u201314 (2016).","journal-title":"Curr. Opin. Cell Biol."},{"key":"76396_CR6","doi-asserted-by":"publisher","first-page":"eaaw1668","DOI":"10.1126\/sciadv.aaw1668","volume":"5","author":"Q Szabo","year":"2019","unstructured":"Szabo, Q., Bantignies, F. & Cavalli, G. Principles of genome folding into topologically associating domains. Sci. Adv. 5, eaaw1668 (2019).","journal-title":"Sci. Adv."},{"key":"76396_CR7","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/nature09380","volume":"467","author":"MH Kagey","year":"2010","unstructured":"Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430\u2013435 (2010).","journal-title":"Nature"},{"key":"76396_CR8","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1016\/j.cell.2016.02.007","volume":"164","author":"J Dekker","year":"2016","unstructured":"Dekker, J. & Mirny, L. The 3D genome as moderator of chromosomal communication. Cell 164, 1110\u20131121 (2016).","journal-title":"Cell"},{"key":"76396_CR9","doi-asserted-by":"crossref","unstructured":"Fosseprez, O. & Cuvier, O. Uncovering the functions and mechanisms of regulatory elements-associated non-coding RNAs. Biochim Biophys. Acta Gene. Regul. Mech. 1867, 195059 (2024).","DOI":"10.1016\/j.bbagrm.2024.195059"},{"key":"76396_CR10","doi-asserted-by":"crossref","unstructured":"Barshad, G. et al. RNA polymerase II dynamics shape enhancer-promoter interactions. Nat. Genet. 55, 1370\u20131380 (2023).","DOI":"10.1038\/s41588-023-01442-7"},{"key":"76396_CR11","doi-asserted-by":"crossref","unstructured":"Zhang, S., Ubelmesser, N., Barbieri, M. & Papantonis, A. Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Nat. Genet. 55, 832\u2013840 (2023).","DOI":"10.1038\/s41588-023-01364-4"},{"key":"76396_CR12","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.molcel.2019.07.039","volume":"76","author":"AS Hansen","year":"2019","unstructured":"Hansen, A. S. et al. Distinct classes of chromatin loops revealed by deletion of an RNA-binding region in CTCF. Mol. Cell 76, 395\u2013411 e13 (2019).","journal-title":"Mol. Cell"},{"key":"76396_CR13","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.molcel.2019.08.015","volume":"76","author":"R Saldana-Meyer","year":"2019","unstructured":"Saldana-Meyer, R. et al. RNA interactions are essential for CTCF-mediated genome organization. Mol. Cell 76, 412\u2013422 e5 (2019).","journal-title":"Mol. Cell"},{"key":"76396_CR14","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.cell.2017.09.001","volume":"171","author":"T Isoda","year":"2017","unstructured":"Isoda, T. et al. Non-coding transcription instructs chromatin folding and compartmentalisation to dictate enhancer-promoter communication and T cell fate. Cell 171, 103\u2013119 e18 (2017).","journal-title":"Cell"},{"key":"76396_CR15","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.molcel.2022.01.014","volume":"82","author":"H Luo","year":"2022","unstructured":"Luo, H. et al. HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia. Mol. Cell 82, 833\u2013851 e11 (2022).","journal-title":"Mol. Cell"},{"key":"76396_CR16","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/s41589-019-0422-3","volume":"16","author":"AS Hansen","year":"2020","unstructured":"Hansen, A. S., Amitai, A., Cattoglio, C., Tjian, R. & Darzacq, X. Guided nuclear exploration increases CTCF target search efficiency. Nat. Chem. Biol. 16, 257\u2013266 (2020).","journal-title":"Nat. Chem. Biol."},{"key":"76396_CR17","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/s41586-020-2249-1","volume":"582","author":"Z Cai","year":"2020","unstructured":"Cai, Z. et al. RIC-seq for global in situ profiling of RNA-RNA spatial interactions. Nature 582, 432\u2013437 (2020).","journal-title":"Nature"},{"key":"76396_CR18","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/s41576-018-0013-2","volume":"19","author":"M Schmid","year":"2018","unstructured":"Schmid, M. & Jensen, T. H. Controlling nuclear RNA levels. Nat. Rev. Genet. 19, 518\u2013529 (2018).","journal-title":"Nat. Rev. Genet."},{"key":"76396_CR19","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.molcel.2011.06.028","volume":"43","author":"M Lubas","year":"2011","unstructured":"Lubas, M. et al. Interaction profiling identifies the human nuclear exosome targeting complex. Mol. Cell 43, 624\u2013637 (2011).","journal-title":"Mol. Cell"},{"key":"76396_CR20","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.molcel.2016.09.025","volume":"64","author":"N Meola","year":"2016","unstructured":"Meola, N. et al. Identification of a nuclear exosome decay pathway for processed transcripts. Mol. Cell 64, 520\u2013533 (2016).","journal-title":"Mol. Cell"},{"key":"76396_CR21","doi-asserted-by":"crossref","unstructured":"Ogami, K. et al. An Mtr4\/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repression. Genes. Dev. 31, 1257\u20131271 (2017).","DOI":"10.1101\/gad.302604.117"},{"key":"76396_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42620-9","volume":"14","author":"X Contreras","year":"2023","unstructured":"Contreras, X. et al. PAPgamma associates with the PAXT nuclear exosome to control the abundance of PROMPT ncRNAs. Nat. Commun. 14, 6745 (2023).","journal-title":"Nat. Commun."},{"key":"76396_CR23","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1080\/15476286.2017.1312227","volume":"14","author":"N Meola","year":"2017","unstructured":"Meola, N. & Jensen, T. H. Targeting the nuclear RNA exosome: Poly(A) binding proteins enter the stage. RNA Biol. 14, 820\u2013826 (2017).","journal-title":"RNA Biol."},{"key":"76396_CR24","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1016\/j.celrep.2018.04.061","volume":"23","author":"T Silla","year":"2018","unstructured":"Silla, T., Karadoulama, E., Makosa, D., Lubas, M. & Jensen, T. H. The RNA exosome adaptor ZFC3H1 functionally competes with nuclear export activity to retain target transcripts. Cell Rep. 23, 2199\u20132210 (2018).","journal-title":"Cell Rep."},{"key":"76396_CR25","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/cr.2018.1","volume":"28","author":"J Yan","year":"2018","unstructured":"Yan, J. et al. Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. Cell Res. 28, 204\u2013220 (2018).","journal-title":"Cell Res."},{"key":"76396_CR26","doi-asserted-by":"publisher","first-page":"e1003382","DOI":"10.1371\/journal.pgen.1003382","volume":"9","author":"CA Schaaf","year":"2013","unstructured":"Schaaf, C. A. et al. Genome-wide control of RNA polymerase II activity by cohesin. PLoS Genet. 9, e1003382 (2013).","journal-title":"PLoS Genet."},{"key":"76396_CR27","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1093\/nar\/gkw1114","volume":"45","author":"C Cubenas-Potts","year":"2017","unstructured":"Cubenas-Potts, C. et al. Different enhancer classes in Drosophila bind distinct architectural proteins and mediate unique chromatin interactions and 3D architecture. Nucleic Acids Res. 45, 1714\u20131730 (2017).","journal-title":"Nucleic Acids Res."},{"key":"76396_CR28","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.molcel.2013.12.029","volume":"53","author":"J Liang","year":"2014","unstructured":"Liang, J. et al. Chromatin immunoprecipitation indirect peaks highlight long-range interactions of insulator proteins and Pol II pausing. Mol. Cell 53, 672\u2013681 (2014).","journal-title":"Mol. Cell"},{"key":"76396_CR29","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1016\/j.cell.2014.11.021","volume":"159","author":"SS Rao","year":"2014","unstructured":"Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665\u20131680 (2014).","journal-title":"Cell"},{"key":"76396_CR30","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/nature22063","volume":"544","author":"GA Busslinger","year":"2017","unstructured":"Busslinger, G. A. et al. Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl. Nature 544, 503\u2013507 (2017).","journal-title":"Nature"},{"key":"76396_CR31","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/nature11884","volume":"494","author":"F Lai","year":"2013","unstructured":"Lai, F. et al. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497\u2013501 (2013).","journal-title":"Nature"},{"key":"76396_CR32","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.1093\/nar\/gkw1220","volume":"45","author":"S Rahman","year":"2017","unstructured":"Rahman, S. et al. Single-cell profiling reveals that eRNA accumulation at enhancer-promoter loops is not required to sustain transcription. Nucleic Acids Res. 45, 3017\u20133030 (2017).","journal-title":"Nucleic Acids Res."},{"key":"76396_CR33","doi-asserted-by":"publisher","first-page":"e1006950","DOI":"10.1371\/journal.ppat.1006950","volume":"14","author":"X Contreras","year":"2018","unstructured":"Contreras, X. et al. Nuclear RNA surveillance complexes silence HIV-1 transcription. PLoS Pathog. 14, e1006950 (2018).","journal-title":"PLoS Pathog."},{"key":"76396_CR34","doi-asserted-by":"publisher","first-page":"eabb2947","DOI":"10.1126\/sciadv.abb2947","volume":"7","author":"K Salifou","year":"2021","unstructured":"Salifou, K. et al. Chromatin-associated MRN complex protects highly transcribing genes from genomic instability. Sci. Adv. 7, eabb2947 (2021).","journal-title":"Sci. Adv."},{"key":"76396_CR35","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754\u20131760 (2009).","journal-title":"Bioinformatics"},{"key":"76396_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6531","volume":"5","author":"B Stadelmayer","year":"2014","unstructured":"Stadelmayer, B. et al. Integrator complex regulates NELF-mediated RNA polymerase II pause\/release and processivity at coding genes. Nat. Commun. 5, 5531 (2014).","journal-title":"Nat. Commun."},{"key":"76396_CR37","doi-asserted-by":"crossref","unstructured":"Wickham, H. ggplot2: Elegant Graphics for Data Analysis. (Springer-Verlag, New York, 2016).","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"76396_CR38","doi-asserted-by":"crossref","unstructured":"Stempor, P. & Ahringer, J. SeqPlots - Interactive software for exploratory data analyses, pattern discovery and visualization in genomics. Wellcome Open Res. 1, 14 (2016).","DOI":"10.12688\/wellcomeopenres.10004.1"},{"key":"76396_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12514","volume":"7","author":"S Kinkley","year":"2016","unstructured":"Kinkley, S. et al. reChIP-seq reveals widespread bivalency of H3K4me3 and H3K27me3 in CD4(+) memory T cells. Nat. Commun. 7, 12514 (2016).","journal-title":"Nat. Commun."},{"key":"76396_CR40","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.15252\/embj.201798004","volume":"36","author":"G Wutz","year":"2017","unstructured":"Wutz, G. et al. Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins. EMBO J. 36, 3573\u20133599 (2017).","journal-title":"EMBO J."},{"key":"76396_CR41","doi-asserted-by":"crossref","unstructured":"Heurteau, A. et al. Insulator-based loops mediate the spreading of H3K27me3 over distant micro-domains, repressing euchromatin genes. Genome. Biol. 21, 193 (2020).","DOI":"10.1186\/s13059-020-02106-z"},{"key":"76396_CR42","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.cels.2015.07.012","volume":"3","author":"NC Durand","year":"2016","unstructured":"Durand, N. C. et al. Juicebox provides a visualization system for Hi-C contact maps with unlimited zoom. Cell Syst. 3, 99\u2013101 (2016).","journal-title":"Cell Syst."},{"key":"76396_CR43","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/nature12787","volume":"507","author":"R Andersson","year":"2014","unstructured":"Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455\u2013461 (2014).","journal-title":"Nature"},{"key":"76396_CR44","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1126\/science.1259418","volume":"347","author":"E Arner","year":"2015","unstructured":"Arner, E. et al. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347, 1010\u20131014 (2015).","journal-title":"Science"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76396-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76396-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76396-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:03:51Z","timestamp":1788519831000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76396-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["76396"],"URL":"https:\/\/doi.org\/10.1038\/s41467-026-76396-5","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]},"assertion":[{"value":"28 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"9481"}}