{"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":1790625348329,"version":"4.1.0"},"reference-count":63,"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\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["5R37AI077595"],"award-info":[{"award-number":["5R37AI077595"]}],"id":[{"id":"10.13039\/100000002","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                    Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) of immunoglobulin heavy chain (HC) variable region exons in germinal center (GC) B cells, allowing selection of affinity-matured B cell receptors. The V(D)J exon location is \"privileged\" for SHM targeting of diverse sequences within it. In analogy to the related HC class switch recombination center, we proposed that cohesin-mediated loop extrusion juxtaposes widely separated enhancers, including 3\u2032\n                    <jats:italic toggle=\"yes\">Igh<\/jats:italic>\n                    regulatory region (\"3\u2032RR\"), with the V(D)J exon in GC B cells to establish a SHM-center (SHM-C) \"privileged\" for AID access. To test this hypothesis, we employed a human RAMOS GC B lymphoma cell SHM model with inducible AID expression in which we targeted an unmutated mouse HC V(D)J exon in place of its human counterpart. Activation of AID expression in this cycling RAMOS line for 10 d led to robust SHM accumulation in the mouse V(D)J exon with a pattern similar to that in mouse GC B cells. In this model, the mouse V(D)J exon was indeed juxtaposed to the two human 3\u2032RRs and other elements consistent with SHM-C formation. While deletion of individual 3\u2032RRs had little effect, deletion of both greatly reduced SHM, but left V(D)J exon transcription unabated. Moreover, the SHM-C and SHM accumulation remained intact over a 10-d period in viably G1-arrested and viably G1-arrested RAD21 (cohesin)-depleted versions of the model. We discuss implications for SHM-C structure and function, its long-term functional stability in the absence of the loop extrusion process proposed to assemble it, and for 3\u2032RR SHM functions beyond transcriptional activation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2625638123","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":["Human antibody heavy chain variable region exon interacts with the 3\u2032 regulatory region to form a stable somatic hypermutation center"],"prefix":"10.1073","volume":"123","author":[{"given":"Ying","family":"Guan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00dvg7y05","id-type":"ROR","asserted-by":"publisher"}],"name":"Howard Hughes Medical Institute, Boston Children's 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C.","year":"2026","unstructured":"M. C. Lauring , Co-option of retrotransposons promotes antibody diversification. Cell 189, 1\u201321 (2026).","journal-title":"Cell"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03387-6"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80298-8"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.09.017"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024392118"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1598"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007968"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.04.034"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3958"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.11.008"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.043"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.086"},{"key":"e_1_3_4_63_2","unstructured":"F. W. Alt X. Chen Y. Guan Data from \"Human antibody heavy chain variable region exon interacts with 3\u2032 regulatory region to form a stable somatic hypermutation center.\" Gene Expression Omnibus (GEO) NCBI. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE339325. Deposited 11 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.2625638123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:03:42Z","timestamp":1790622222000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2625638123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":63,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2026,10,6]]}},"alternative-id":["10.1073\/pnas.2625638123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2625638123","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":"2026-07-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-24","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":"e2625638123"}}