Schübeler D, Francastel C, Cimbora D M, Reik A, Martin D I, Groudine M
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Genes Dev. 2000 Apr 15;14(8):940-50.
We have investigated the mechanism, structural correlates, and cis-acting elements involved in chromatin opening and gene activation, using the human beta-globin locus as a model. Full transcriptional activity of the human beta-globin locus requires the locus control region (LCR), composed of a series of nuclease hypersensitive sites located upstream of this globin gene cluster. Our previous analysis of naturally occurring and targeted LCR deletions revealed that chromatin opening and transcriptional activity in the endogenous beta-globin locus are dissociable and dependent on distinct cis-acting elements. We now report that general histone H3/H4 acetylation and relocation of the locus away from centromeric heterochromatin in the interphase nucleus are correlated and do not require the LCR. In contrast, LCR-dependent promoter activation is associated with localized histone H3 hyperacetylation at the LCR and the transcribed beta-globin-promoter and gene. On the basis of these results, we suggest a multistep model for gene activation; localization away from centromeric heterochromatin is required to achieve general hyperacetylation and an open chromatin structure of the locus, whereas a mechanism involving LCR/promoter histone H3 hyperacetylation is required for high-level transcription of the beta-globin genes.
我们以人类β-珠蛋白基因座为模型，研究了参与染色质开放和基因激活的机制、结构关联及顺式作用元件。人类β-珠蛋白基因座的完全转录活性需要基因座控制区（LCR），它由位于该珠蛋白基因簇上游的一系列核酸酶超敏位点组成。我们之前对天然存在的和靶向的LCR缺失的分析表明，内源性β-珠蛋白基因座中的染色质开放和转录活性是可分离的，且依赖于不同的顺式作用元件。我们现在报告，一般的组蛋白H3/H4乙酰化以及该基因座在间期核中远离着丝粒异染色质的重新定位是相关的，且不需要LCR。相反，LCR依赖的启动子激活与LCR以及转录的β-珠蛋白启动子和基因处的局部组蛋白H3高乙酰化有关。基于这些结果，我们提出了一个基因激活的多步骤模型；远离着丝粒异染色质的定位是实现该基因座的一般高乙酰化和开放染色质结构所必需的，而β-珠蛋白基因的高水平转录则需要一种涉及LCR/启动子组蛋白H3高乙酰化的机制。
