2024
J Exp Med. 2024 Aug 5;221(8):e20232160. doi: 10.1084/jem.20232160. Epub 2024 Jun 6.
Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement
Department of Immunology, Central Clinical School, Monash University, Melbourne, Australia. Ozgene Pty Ltd. , Bentley, Australia. Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia. Immunity Program, Biomedicine Discovery Institute, Monash University , Clayton, Australia. Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. Department of Medical Biology, University of Melbourne, Parkville, Australia.
Service type: Knockout mice
Abstract
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.
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