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Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)\u2212155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase,\n                    <jats:italic>Kdm2a<\/jats:italic>\n                    , whose expression increases in response to hypoxia. The miR-155-\n                    <jats:italic>Kdm2a<\/jats:italic>\n                    interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-54937-0","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T08:15:47Z","timestamp":1733213747000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2511-0444","authenticated-orcid":false,"given":"Rinako","family":"Nakagawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2582-6602","authenticated-orcid":false,"given":"Miriam","family":"Llorian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita","family":"Varsani-Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Probir","family":"Chakravarty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannie M.","family":"Camarillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Barry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil P.","family":"Blackledge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Duddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8815-3372","authenticated-orcid":false,"given":"Neil L.","family":"Kelleher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8726-7888","authenticated-orcid":false,"given":"Robert J.","family":"Klose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3801-9896","authenticated-orcid":false,"given":"Martin","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8239-7184","authenticated-orcid":false,"given":"Dinis P.","family":"Calado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"54937_CR1","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1016\/0092-8674(91)90289-B","volume":"67","author":"C Berek","year":"1991","unstructured":"Berek, C., Berger, A. & Apel, M. 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