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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,6,27]]},"abstract":"<jats:p>\n                    Immunoglobulin heavy chain variable region exons are assembled in progenitor-B cells, from V\n                    <jats:sub>H<\/jats:sub>\n                    , D, and J\n                    <jats:sub>H<\/jats:sub>\n                    gene segments located in separate clusters across the\n                    <jats:italic>Igh<\/jats:italic>\n                    locus. RAG endonuclease initiates V(D)J recombination from a J\n                    <jats:sub>H<\/jats:sub>\n                    -based recombination center (RC). Cohesin-mediated extrusion of upstream chromatin past RC-bound RAG presents Ds for joining to J\n                    <jats:sub>H<\/jats:sub>\n                    s to form a DJ\n                    <jats:sub>H<\/jats:sub>\n                    -RC.\n                    <jats:italic>Igh<\/jats:italic>\n                    has a provocative number and organization of CTCF-binding elements (CBEs) that can impede loop extrusion. Thus,\n                    <jats:italic>Igh<\/jats:italic>\n                    has two divergently oriented CBEs (CBE1 and CBE2) in the IGCR1 element between the V\n                    <jats:sub>H<\/jats:sub>\n                    and D\/J\n                    <jats:sub>H<\/jats:sub>\n                    domains, over 100 CBEs across the V\n                    <jats:sub>H<\/jats:sub>\n                    domain convergent to CBE1, and 10 clustered 3\u2032\n                    <jats:italic>Igh<\/jats:italic>\n                    -CBEs convergent to CBE2 and V\n                    <jats:sub>H<\/jats:sub>\n                    CBEs. IGCR1 CBEs segregate D\/J\n                    <jats:sub>H<\/jats:sub>\n                    and V\n                    <jats:sub>H<\/jats:sub>\n                    domains by impeding loop extrusion-mediated RAG-scanning. Downregulation of WAPL, a cohesin unloader, in progenitor-B cells neutralizes CBEs, allowing DJ\n                    <jats:sub>H<\/jats:sub>\n                    -RC-bound RAG to scan the V\n                    <jats:sub>H<\/jats:sub>\n                    domain and perform V\n                    <jats:sub>H<\/jats:sub>\n                    -to-DJ\n                    <jats:sub>H<\/jats:sub>\n                    rearrangements. To elucidate potential roles of IGCR1-based CBEs and 3\u2032\n                    <jats:italic>Igh<\/jats:italic>\n                    -CBEs in regulating RAG-scanning and elucidate the mechanism of the ordered transition from D-to-J\n                    <jats:sub>H<\/jats:sub>\n                    to V\n                    <jats:sub>H<\/jats:sub>\n                    -to-DJ\n                    <jats:sub>H<\/jats:sub>\n                    recombination, we tested effects of inverting and\/or deleting IGCR1 or 3\u2032\n                    <jats:italic>Igh<\/jats:italic>\n                    -CBEs in mice and\/or progenitor-B cell lines. These studies revealed that normal IGCR1 CBE orientation augments RAG-scanning impediment activity and suggest that 3\u2032\n                    <jats:italic>Igh<\/jats:italic>\n                    -CBEs reinforce ability of the RC to function as a dynamic loop extrusion impediment to promote optimal RAG scanning activity. Finally, our findings indicate that ordered V(D)J recombination can be explained by a gradual WAPL downregulation mechanism in progenitor-B cells as opposed to a strict developmental switch.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2306564120","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T13:54:41Z","timestamp":1687269281000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Contribution of the IGCR1 regulatory element and the 3\u2032\n                    <i>Igh<\/i>\n                    CTCF-binding elements to regulation of\n                    <i>Igh<\/i>\n                    V(D)J recombination"],"prefix":"10.1073","volume":"120","author":[{"given":"Zhuoyi","family":"Liang","sequence":"first","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam Yongxin","family":"Ye","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry G.","family":"Lin","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunguang","family":"Guo","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Qiang","family":"Dai","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8431-5469","authenticated-orcid":false,"given":"Zhaoqing","family":"Ba","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick W.","family":"Alt","sequence":"additional","affiliation":[{"name":"HHMI, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,6,20]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"1","article-title":"The role of chromatin loop extrusion in antibody diversification","volume":"9","author":"Zhang Y.","year":"2022","unstructured":"Y. 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