{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:55:48Z","timestamp":1790625348264,"version":"4.1.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"40","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32300729"],"award-info":[{"award-number":["32300729"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22137004 82430109 and 22541704"],"award-info":[{"award-number":["22137004 82430109 and 22541704"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>\n                    Cyclic GMP\u2013AMP synthase (cGAS) is a cytosolic DNA sensor that detects aberrant DNA and activates the STING-dependent innate immune response. Although cGAS is predominantly localized in the nucleus under physiological conditions, its nuclear function remains incompletely understood. Here, we identify nuclear cGAS as a transcriptional repressor that restrains inflammatory gene expression independently of STING signaling. Using macrophages challenged with lipopolysaccharide (LPS), we found that cGAS selectively suppresses the transcription of primary response genes, including\n                    <jats:italic toggle=\"yes\">Cxcl1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Tnf<\/jats:italic>\n                    . Mechanistically, this activity requires nucleosome binding but not cGAS enzymatic signaling. Upon inflammatory stimulation, the transcription factor PU.1 recruits cGAS to target promoters, where the carboxyl-terminal domain of cGAS interacts with histone deacetylase 1 (HDAC1). This complex promotes deacetylation of H3K27ac and restricts transcriptional activation of inflammatory genes. Genome-wide chromatin accessibility and occupancy analyses revealed that cGAS-dependent transcriptional repression occurs at a distinct subset of PU.1-associated inflammatory loci. Functionally, macrophage-specific\n                    <jats:italic toggle=\"yes\">Hdac1<\/jats:italic>\n                    deficiency phenocopied the exaggerated inflammatory responses observed in\n                    <jats:italic toggle=\"yes\">Cgas<\/jats:italic>\n                    -deficient mice during endotoxemia, whereas the pathogenic effects of\n                    <jats:italic toggle=\"yes\">Hdac1<\/jats:italic>\n                    loss were abolished in the absence of\n                    <jats:italic toggle=\"yes\">Cgas<\/jats:italic>\n                    . Moreover, increased mortality and neutrophil infiltration in\n                    <jats:italic toggle=\"yes\">Cgas-<\/jats:italic>\n                    deficient mice were rescued by deletion of\n                    <jats:italic toggle=\"yes\">Csf3r<\/jats:italic>\n                    . Together, these findings uncover a previously unrecognized transcriptional function of nuclear cGAS and identify nuclear cGAS as an intrinsic brake that restrains excessive inflammatory responses.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2601665123","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:02:56Z","timestamp":1790622176000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Nuclear cGAS inhibits stimulation-induced inflammatory gene transcription via HDAC1"],"prefix":"10.1073","volume":"123","author":[{"given":"Shangze","family":"Gao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University","place":["Beijing, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaiting","family":"Yan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7796-8891","authenticated-orcid":false,"given":"Shengping","family":"Hou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013e4n276","id-type":"ROR","asserted-by":"publisher"}],"name":"Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9762-4818","authenticated-orcid":false,"given":"Hang","family":"Yin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/022k4wk35","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Advanced Study, Beijing Normal University","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/022k4wk35","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Chemistry, Beijing Normal University","place":["Beijing, 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Gao H. Li H. Yin Nuclear cGAS inhibits stimulation-induced inflammatory gene transcription via recruiting HDAC1. Gene Expression Omnibus. https:\/\/ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE346403. Deposited 9 September 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2601665123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:04:14Z","timestamp":1790622254000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2601665123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":52,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2026,10,6]]}},"alternative-id":["10.1073\/pnas.2601665123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2601665123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]},"assertion":[{"value":"2026-01-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2601665123"}}