Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement

Ding, Z; Hagan, M; Yan, F; Schroer, NWY; Polmear, J; Good-Jacobson, KL; Dvorscek, AR; Pitt, C; O&#39;Donnell, K; Nutt, SL; Zotos, D; McKenzie, C; Hill, DL; Robinson, MJ; Quast, I; Koentgen, F; Tarlinton, DM

Author(s): Ding, Z; Hagan, M; Yan, F; Schroer, NWY; Polmear, J; Good-Jacobson, KL; Dvorscek, AR; Pitt, C; O'Donnell, K; Nutt, SL; Zotos, D; McKenzie, C; Hill, DL; Robinson, MJ; Quast, I; Koentgen, F; Tarlinton, DM;
Journal Title: Journal of Experimental Medicine
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.
Publisher: Rockefeller University Press
Keywords: *Ki-67 Antigen/metabolism; Animals; *Chromatin/metabolism/genetics; *B-Lymphocytes/metabolism/immunology; Lymphopoiesis/genetics; Receptors, Antigen, B-Cell/metabolism/genetics; Mice; Gene Rearrangement; Homeodomain Proteins/genetics/metabolism; T-Lymphocytes/metabolism/immunology; Mice, Inbred C57BL; Cell Proliferation/genetics
Research Division(s): Immunology
PubMed ID: 38842525
Publisher's Version: https://doi.org/10.1084/jem.20232160
Open Access at Publisher's Site: https://doi.org/10.1084/jem.20232160
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-06-24 11:29:52

Last Modified: 2024-06-24 11:34:39