{"intvolume":"       122","project":[{"_id":"7bfe6a29-9f16-11ee-852c-c0da5e2045d9","name":"Transcription in 4D: the dynamic interplay between chromatin architecture and gene expression in developing pseudo-embryos","grant_number":"101118866"}],"related_material":{"link":[{"relation":"software","url":"https://github.com/officerredshirt/network_crosstalk"}]},"month":"01","corr_author":"1","file":[{"file_name":"2025_PNAS_Perkins.pdf","file_size":30943709,"checksum":"86a8d25a6e282aeb4128f1d0b86ff911","file_id":"18859","success":1,"creator":"dernst","date_created":"2025-01-20T09:38:32Z","content_type":"application/pdf","access_level":"open_access","date_updated":"2025-01-20T09:38:32Z","relation":"main_file"}],"file_date_updated":"2025-01-20T09:38:32Z","year":"2025","article_number":"e2411887121","pmid":1,"scopus_import":"1","status":"public","acknowledgement":"M.L.P. was supported by the European Molecular Biology Laboratory (EMBL) Interdisciplinary Postdoc Programme (EIPOD4 fellowships), cofunded by Marie SkÅ‚odowska-Curie Actions (Grant Agreement No. 847543). J.C. and M.L.P. were supported by EMBL Core Funding and Theory@EMBL. This work is supported by European Research Council Grant DynaTrans (101118866) to G.T. We would like to thank the members of the J.C. and G.T. groups, especially Natalia Misunou, Michal Hledík, and Réka Borbély, for helpful feedback and discussion. We also thank EMBL IT Services for the use of high performance computing resources.","citation":{"ista":"Perkins ML, Crocker J, Tkačik G. 2025. Chromatin enables precise and scalable gene regulation with factors of limited specificity. Proceedings of the National Academy of Sciences of the United States of America. 122(1), e2411887121.","mla":"Perkins, Mindy Liu, et al. “Chromatin Enables Precise and Scalable Gene Regulation with Factors of Limited Specificity.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 122, no. 1, e2411887121, National Academy of Sciences, 2025, doi:<a href=\"https://doi.org/10.1073/pnas.2411887121\">10.1073/pnas.2411887121</a>.","short":"M.L. Perkins, J. Crocker, G. Tkačik, Proceedings of the National Academy of Sciences of the United States of America 122 (2025).","ama":"Perkins ML, Crocker J, Tkačik G. Chromatin enables precise and scalable gene regulation with factors of limited specificity. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2025;122(1). doi:<a href=\"https://doi.org/10.1073/pnas.2411887121\">10.1073/pnas.2411887121</a>","apa":"Perkins, M. L., Crocker, J., &#38; Tkačik, G. (2025). Chromatin enables precise and scalable gene regulation with factors of limited specificity. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2411887121\">https://doi.org/10.1073/pnas.2411887121</a>","chicago":"Perkins, Mindy Liu, Justin Crocker, and Gašper Tkačik. “Chromatin Enables Precise and Scalable Gene Regulation with Factors of Limited Specificity.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2025. <a href=\"https://doi.org/10.1073/pnas.2411887121\">https://doi.org/10.1073/pnas.2411887121</a>.","ieee":"M. L. Perkins, J. Crocker, and G. Tkačik, “Chromatin enables precise and scalable gene regulation with factors of limited specificity,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 122, no. 1. National Academy of Sciences, 2025."},"tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"publisher":"National Academy of Sciences","date_created":"2025-01-19T23:01:51Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","ddc":["570"],"doi":"10.1073/pnas.2411887121","article_processing_charge":"No","language":[{"iso":"eng"}],"oa_version":"Published Version","external_id":{"pmid":["39793086"]},"author":[{"first_name":"Mindy Liu","full_name":"Perkins, Mindy Liu","last_name":"Perkins"},{"last_name":"Crocker","full_name":"Crocker, Justin","first_name":"Justin"},{"full_name":"Tkačik, Gašper","last_name":"Tkačik","orcid":"0000-0002-6699-1455","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gašper"}],"OA_type":"hybrid","article_type":"original","type":"journal_article","_id":"18850","date_updated":"2025-01-20T09:40:37Z","publication":"Proceedings of the National Academy of Sciences of the United States of America","issue":"1","publication_identifier":{"eissn":["10916490"],"issn":["00278424"]},"has_accepted_license":"1","abstract":[{"lang":"eng","text":"Biophysical constraints limit the specificity with which transcription factors (TFs) can target regulatory DNA. While individual nontarget binding events may be low affinity, the sheer number of such interactions could present a challenge for gene regulation by degrading its precision or possibly leading to an erroneous induction state. Chromatin can prevent nontarget binding by rendering DNA physically inaccessible to TFs, at the cost of energy-consuming remodeling orchestrated by pioneer factors (PFs). Under what conditions and by how much can chromatin reduce regulatory errors on a global scale? We use a theoretical approach to compare two scenarios for gene regulation: one that relies on TF binding to free DNA alone and one that uses a combination of TFs and chromatin-regulating PFs to achieve desired gene expression patterns. We find, first, that chromatin effectively silences groups of genes that should be simultaneously OFF, thereby allowing more accurate graded control of expression for the remaining ON genes. Second, chromatin buffers the deleterious consequences of nontarget binding as the number of OFF genes grows, permitting a substantial expansion in regulatory complexity. Third, chromatin-based regulation productively co-opts nontarget TF binding for ON genes in order to establish a “leaky” baseline expression level, which targeted activator or repressor binding subsequently up- or down-modulates. Thus, on a global scale, using chromatin simultaneously alleviates pressure for high specificity of regulatory interactions and enables an increase in genome size with minimal impact on global expression error."}],"date_published":"2025-01-07T00:00:00Z","OA_place":"publisher","quality_controlled":"1","day":"07","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","volume":122,"department":[{"_id":"GaTk"}],"oa":1,"publication_status":"published","title":"Chromatin enables precise and scalable gene regulation with factors of limited specificity"}