Department of Pathology, University of Michigan, BSRB 2049, 109 Zina Pitcher Dr., Ann Arbor, MI 48109, USA.
Mol Cell Biol. 2011 Apr;31(7):1503-11. doi: 10.1128/MCB.00990-10. Epub 2011 Jan 31.
How distal transcriptional enhancer sequences interact with proximal promoters is poorly understood within the context of chromatin. In this report, we have used the immunoglobulin heavy chain locus to address the role of the PTIP protein in transcription regulation and class switch recombination in B cells, a process that depends on regulated transcription and DNA recombination via Pax5 and distal 3' enhancer sequences. We first show that PTIP is recruited to a Pax5 binding site to promote histone H3 lysine 4 (H3K4) methylation. Using a CD19-Cre driver strain, we deleted PTIP in mature B cells. Loss of PTIP inhibited class switch recombination by suppressing transcription and histone H3K4 methylation at the germ line transcript promoters. In the absence of PTIP, Pax5 binding to the promoter regions is reduced and long-range chromatin interactions between the distal enhancer at the 3' regulatory region and the germ line transcript promoters are not detected. We propose a model whereby PTIP stabilizes the Pax5 DNA interactions that promote chromatin looping and regulate transcriptional responses needed for class switch recombination.
在染色质背景下，远端转录增强子序列如何与近端启动子相互作用还不太清楚。在本报告中，我们使用免疫球蛋白重链基因座来研究 PTIP 蛋白在 B 细胞转录调控和类别转换重组中的作用，该过程依赖于 Pax5 和远端 3' 增强子序列的调节转录和 DNA 重组。我们首先表明，PTIP 被募集到 Pax5 结合位点以促进组蛋白 H3 赖氨酸 4（H3K4）甲基化。使用 CD19-Cre 驱动株，我们在成熟 B 细胞中删除了 PTIP。PTIP 的缺失通过抑制转录和组蛋白 H3K4 在种系转录启动子上的甲基化来抑制类别转换重组。在没有 PTIP 的情况下，Pax5 与启动子区域的结合减少，并且在 3' 调控区的远端增强子和种系转录启动子之间没有检测到长距离染色质相互作用。我们提出了一个模型，即 PTIP 稳定了 Pax5 的 DNA 相互作用，促进了染色质环化，并调节了类别转换重组所需的转录反应。
