加拿大蒙特利尔临床研究所Javier M. Di Noia研究团队宣布他们开发出组蛋白读取器MLLT1和MLLT3集中AID，赋予位点特异性。2026年9月30日出版的《自然》杂志发表了这项成果。

活化诱导胞苷脱氨酶（AID）通过免疫球蛋白（Ig）基因的类别转换重组和体细胞超突变驱动抗体多样化，但其脱靶致突变活性促进B细胞淋巴瘤的发生。AID如何选择性突变Ig基因座和一组有限的其他基因，仍不清楚。转录是AID活性所必需的，但大多数被转录的基因并未发生突变，而且AID占据的基因座多于其突变的基因座。在此，研究人员鉴定出超级延伸复合物的组蛋白阅读器MLLT1和MLLT3是AID选择性活性的决定因素。MLLT1和MLLT3的联合缺失消除了所有依赖AID的致突变过程，重现了AID缺陷。小鼠和人类B细胞中发生AID突变的基因组区域，被MLLT1和MLLT3的高占据（MLLT1/MLLT3^high）精确标记。删除这两个阅读器后的转录变化轻微，无法解释AID活性的丧失。机制上，MLLT1和MLLT3对于全局AID染色质锚定并非必需，但在启动子区域下游局部富集AID。两个阅读器均与AID结合并冗余发挥作用，但MLLT1通过其内在无序区在小鼠中起主导作用，该区域促进选择性浓缩AID的凝聚体形成。将AID与MLLT1或MLLT3融合，足以在Mllt1/Mllt3缺失细胞中恢复类别转换重组和突变发生。这些发现揭示，局部MLLT1/MLLT3^high依赖性富集通过空间限制和浓缩AID活性（可能通过凝聚体形成），在受限的基因组区域子集中许可AID发挥作用。

附：英文原文

Title: Histone readers MLLT1 and MLLT3 concentrate AID to confer locus specificity

Author: Seija, No, Gannon, Sophia, Hfner, Kra A., Gemeinhardt, Tim M., Ridani, Jana, Alvarez, Diego, Provencher, Mlanie, Subramani, Poorani Ganesh, Poitras, Christian, Piskor, Eva-Maria, Mry, Tarik, Vonniessen, Nicholas, Mazer, Bruce, Navarrette, Marcelo A., Francis, Nicole J., Robert, Franois, Di Noia, Javier M.

Issue&Volume: 2026-09-30

Abstract: Activation-induced deaminase (AID) drives antibody diversification through class-switch recombination and somatic hypermutation of the immunoglobulin (Ig) genes, but its off-target mutagenic activity contributes to B cell lymphoma1,2,3,4,5. How AID selectively mutates Ig loci and a restricted set of other genes remains unknown. Transcription is required for AID activity, but most transcribed genes are not mutated1,5,6,7, and AID occupies more loci than it mutates7,8,9. Here we identify the super elongation complex histone readers MLLT1 and MLLT3 as determinants of selective AID activity. Combined loss of MLLT1 and MLLT3 abolishes all AID-dependent mutagenic processes, recapitulating AID deficiency. AID-mutated genomic regions in mouse and human B cells are precisely marked by high MLLT1 and MLLT3 occupancy (MLLT1/MLLT3high). Transcriptional changes after deleting both readers are modest and cannot explain the AID activity loss. Mechanistically, MLLT1 and MLLT3 are dispensable for global AID chromatin tethering but locally enrich AID downstream from promoter regions. Both readers bind to AID and act redundantly, but MLLT1 has a dominant role in mice through its intrinsically disordered region, which promotes condensates that selectively concentrate AID. Fusing AID to MLLT1 or MLLT3 is sufficient to restore class-switch recombination and mutagenesis in Mllt1/Mllt3/ cells. These findings reveal that local MLLT1/MLLT3high-dependent enrichment licenses AID at a restricted subset of genomic regions by spatially confining and concentrating its activity, probably through condensate formation.

DOI: 10.1038/s41586-026-11087-1

Source: https://www.nature.com/articles/s41586-026-11087-1