Department of Pathology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11930-5. doi: 10.1073/pnas.1004962107. Epub 2010 Jun 14.
BCL6 encodes a transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis. Although its promoter has been well studied, little is known concerning its possible regulation by more distal elements. To gain such information, we mapped critical histone modifications associated with active transcription within BCL6 as well as far upstream sequences at nucleosomal resolution in B-cell lines and in normal naive and GC B cells. Promoter-associated and intronic CpG islands (CGIs) in BCL6 showed a reciprocal pattern of histone modifications. Gene expression correlated with a paradoxical loss from the intronic CGI of histone H3 lysine-4 trimethylation, normally associated with transcription, suggesting that the intronic CGI may interfere with transcription. In an approximately 110-kb region extending 150-260 kb upstream of BCL6, highly active histone modifications were present only in normal GC B cells and a GC B-cell line; this region overlaps with an alternative breakpoint region for chromosomal translocations and contains a GC-specific noncoding RNA gene. By chromosome conformation capture, we determined that the BCL6 promoter interacts with this distant upstream region. It is likely that transcriptional enhancers in this region activate BCL6 and overcome strong autorepression in GC B cells.
BCL6 编码一种转录抑制因子，对于生发中心（GC）反应是必需的，并且在淋巴瘤发生中很重要。尽管其启动子已得到很好的研究，但对于其可能通过更远端的元件进行调节知之甚少。为了获得这些信息，我们以核小体分辨率在 B 细胞系和正常幼稚及 GC B 细胞中绘制了与 BCL6 中活跃转录相关的关键组蛋白修饰以及远上游序列。BCL6 中的启动子相关和内含子 CpG 岛（CGI）显示出组蛋白修饰的相反模式。基因表达与内含子 CGI 中组蛋白 H3 赖氨酸-4 三甲基化的反常缺失相关，通常与转录相关，表明内含子 CGI 可能干扰转录。在大约 110kb 的区域中，BCL6 的上游延伸 150-260kb，只有在正常 GC B 细胞和 GC B 细胞系中存在高度活跃的组蛋白修饰；该区域与染色体易位的替代断点区域重叠，并包含一个 GC 特异性非编码 RNA 基因。通过染色体构象捕获，我们确定 BCL6 启动子与这个遥远的上游区域相互作用。很可能是该区域中的转录增强子激活了 BCL6，并克服了 GC B 细胞中的强烈自身抑制。
