Department of Immunology, Central Clinical School, Monash University, Melbourne, Australia.
Ozgene Pty Ltd. , Bentley, Australia.
J Exp Med. 2024 Aug 5;221(8). doi: 10.1084/jem.20232160. Epub 2024 Jun 6.
The proliferation marker Ki67 has been attributed critical functions in maintaining mitotic chromosome morphology and heterochromatin organization during the cell cycle, indicating a potential role in developmental processes requiring rigid cell-cycle control. Here, we discovered that despite normal fecundity and organogenesis, germline deficiency in Ki67 resulted in substantial defects specifically in peripheral B and T lymphocytes. This was not due to impaired cell proliferation but rather to early lymphopoiesis at specific stages where antigen-receptor gene rearrangements occurred. We identified that Ki67 was required for normal global chromatin accessibility involving regulatory regions of genes critical for checkpoint stages in B cell lymphopoiesis. In line with this, mRNA expression of Rag1 was diminished and gene rearrangement was less efficient in the absence of Ki67. Transgenes encoding productively rearranged immunoglobulin heavy and light chains complemented Ki67 deficiency, completely rescuing early B cell development. Collectively, these results identify a unique contribution from Ki67 to somatic antigen-receptor gene rearrangement during lymphopoiesis.
增殖标志物 Ki67 在维持有丝分裂染色体形态和异染色质组织方面具有关键功能，这表明其在需要严格细胞周期控制的发育过程中可能具有潜在作用。在这里，我们发现尽管生殖系 Ki67 缺陷小鼠具有正常的繁殖力和器官发生，但特异性地在外周 B 和 T 淋巴细胞中出现了严重缺陷。这不是由于细胞增殖受损，而是由于在发生抗原受体基因重排的特定阶段早期的淋巴发生。我们发现 Ki67 对于正常的全局染色质可及性是必需的，这涉及到 B 细胞淋巴发生中检查点阶段的关键基因的调控区域。与此一致的是，Rag1 的 mRNA 表达减少，并且在缺乏 Ki67 的情况下基因重排效率较低。编码有效重排的免疫球蛋白重链和轻链的转基因可补充 Ki67 缺陷，完全挽救早期 B 细胞发育。总的来说，这些结果表明 Ki67 在淋巴发生过程中的体细胞抗原受体基因重排中具有独特的作用。
