Laboratory of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Laboratory of Molecular Biology & Immunology, National Institute on Aging, NIH, Baltimore, MD, USA.
Cell Rep. 2024 Jul 23;43(7):114456. doi: 10.1016/j.celrep.2024.114456. Epub 2024 Jul 9.
The rearrangement and expression of the immunoglobulin μ heavy chain (Igh) gene require communication of the intragenic Eμ and 3' regulatory region (RR) enhancers with the variable (V) gene promoter. Eμ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eμ wild-type enhancer and that of Eμ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network. We found that MSL2 recruitment depends on YY1 and that gene knockout of Msl2 in primary pre-B cells reduces μ gene expression and chromatin looping of Eμ to the 3' RR enhancer and V promoter. Moreover, Mof heterozygosity in mice impaired μ expression and early B cell differentiation. Together, these data suggest that the MSL/MOF complex regulates Igh gene expression by augmenting YY1-mediated enhancer-promoter communication.
免疫球蛋白 μ 重链（Igh）基因的重排和表达需要基因内的 Eμ 和 3' 调控区（RR）增强子与可变（V）基因启动子进行通讯。Eμ 与转录因子 YY1 的结合已被牵连到增强子-启动子通讯中，但 YY1 蛋白网络仍然不清楚。通过分析 1kb Eμ 野生型增强子的综合蛋白质组和缺乏 YY1 结合位点的 Eμ 的蛋白质组，我们将雄性特异性致死（MSL）/MOF 复合物鉴定为 YY1 蛋白网络的一个组成部分。我们发现 MSL2 的募集取决于 YY1，并且在原代 pre-B 细胞中敲除 Msl2 会降低 μ 基因的表达和 Eμ 到 3'RR 增强子和 V 启动子的染色质环化。此外，小鼠中 MOF 的杂合性会损害 μ 的表达和早期 B 细胞分化。总的来说，这些数据表明 MSL/MOF 复合物通过增强 YY1 介导的增强子-启动子通讯来调节 Igh 基因的表达。
