Madisen L, Krumm A, Hebbes T R, Groudine M
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, Washington, USA.
Mol Cell Biol. 1998 Nov;18(11):6281-92. doi: 10.1128/MCB.18.11.6281.
In chromosome translocations characteristic of Burkitt lymphomas (BL) and murine plasmacytomas, c-myc genes become juxtaposed to immunoglobulin heavy-chain (IgH) sequences, resulting in aberrant c-myc transcription. Translocated c-myc alleles that retain the first exon exhibit increased transcription from the normally minor c-myc promoter, P1, and increased transcriptional elongation through inherent pause sites proximal to the major c-myc promoter, P2. We recently demonstrated that a cassette derived from four DNase I-hypersensitive sites (HS1234) in the 3'Calpha region of the IgH locus functions as an enhancer-locus control region (LCR) and directs a similar pattern of deregulated expression of linked c-myc genes in BL and plasmacytoma cell lines. Here, we report that the HS1234 enhancer-LCR mediates a widespread increase in histone acetylation along linked c-myc genes in Raji BL cells. Significantly, the increase in acetylation was not restricted to nucleosomes within the promoter region but also was apparent upstream and downstream of the transcription start sites as well as along vector sequences. Histone hyperacetylation of control c-myc genes, which was induced by the deacetylase inhibitor trichostatin A, mimics the effect of the HS1234 enhancer on expression from the c-myc P2 promoter, but not that from the P1 promoter. These results suggest that the HS1234 enhancer stimulates transcription of c-myc by a combination of mechanisms. Whereas HS1234 activates expression from the P2 promoter through a mechanism that includes increased histone acetylation, a general increase in histone acetylation is not sufficient to explain the HS1234-mediated activation of transcription from P1.
在伯基特淋巴瘤（BL）和鼠浆细胞瘤特有的染色体易位中，c-myc基因与免疫球蛋白重链（IgH）序列并列，导致c-myc异常转录。保留第一个外显子的易位c-myc等位基因表现出从正常情况下较小的c-myc启动子P1转录增加，以及通过主要c-myc启动子P2近端的固有暂停位点转录延伸增加。我们最近证明，源自IgH基因座3'Calpha区域四个DNase I超敏位点（HS1234）的一个盒式结构作为增强子-基因座控制区（LCR），并在BL和浆细胞瘤细胞系中指导连锁c-myc基因的类似失调表达模式。在这里，我们报告HS1234增强子-LCR介导Raji BL细胞中连锁c-myc基因上组蛋白乙酰化的广泛增加。值得注意的是，乙酰化的增加不仅限于启动子区域内的核小体，在转录起始位点的上游和下游以及载体序列上也很明显。由去乙酰化酶抑制剂曲古抑菌素A诱导的对照c-myc基因的组蛋白高乙酰化模拟了HS1234增强子对c-myc P2启动子表达的影响，但对P1启动子的表达没有影响。这些结果表明，HS1234增强子通过多种机制刺激c-myc的转录。虽然HS1234通过包括增加组蛋白乙酰化在内的机制激活P2启动子的表达，但组蛋白乙酰化的普遍增加不足以解释HS1234介导的P1转录激活。
