Yan Chunhong, Boyd Douglas D
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Mol Cell Biol. 2006 Sep;26(17):6357-71. doi: 10.1128/MCB.00311-06.
Histone modifications are associated with distinct transcription states and serve as heritable epigenetic markers for chromatin structure and function. While H3 K9 methylation defines condensed heterochromatin that is able to silence a nearby gene, how gene silencing within euchromatin regions is achieved remains elusive. We report here that histone H3 K4 methylation or K9/K14 acetylation defines distinct chromatin regions permissive or nonpermissive for transgene expression. A permissive chromatin region is enriched in H3 K4 methylation and H3 acetylation, while a nonpermissive region is poor in or depleted of these two histone modifications. The histone modification states of the permissive chromatin can spread to transgenic promoters. However, de novo histone H3 acetylation and H3 K4 methylation at a transgenic promoter in a nonpermissive chromatin region are stochastic, leading to variegated transgene expression. Moreover, nonpermissive chromatin progressively silences a transgene, an event that is accompanied by the reduction of H3 K4 methylation and H3 acetylation levels at the transgenic promoter. These repressive effects of nonpermissive chromatin cannot be completely countered by strong transcription activators, indicating the dominance of the chromatin effects. We therefore propose a model in which histone H3 acetylation and H3 K4 methylation localized to discrete sites in the mammalian genome mark distinct chromatin functions that dictate transgene expression or silencing.
组蛋白修饰与不同的转录状态相关联，并作为染色质结构和功能的可遗传表观遗传标记。虽然H3 K9甲基化定义了能够使附近基因沉默的浓缩异染色质，但常染色质区域内的基因沉默是如何实现的仍不清楚。我们在此报告，组蛋白H3 K4甲基化或K9/K14乙酰化定义了对转基因表达允许或不允许的不同染色质区域。允许的染色质区域富含H3 K4甲基化和H3乙酰化，而不允许的区域则缺乏或耗尽这两种组蛋白修饰。允许的染色质的组蛋白修饰状态可以扩散到转基因启动子。然而，在不允许的染色质区域中，转基因启动子处的从头H3乙酰化和H3 K4甲基化是随机的，导致转基因表达的斑驳现象。此外，不允许的染色质会逐渐使转基因沉默，这一事件伴随着转基因启动子处H3 K4甲基化和H3乙酰化水平的降低。不允许的染色质的这些抑制作用不能被强转录激活剂完全抵消，这表明染色质效应的主导地位。因此，我们提出了一个模型，其中定位于哺乳动物基因组离散位点的组蛋白H3乙酰化和H3 K4甲基化标记了决定转基因表达或沉默的不同染色质功能。
