Fromm George, de Vries Christina, Byron Rachel, Fields Jennifer, Fiering Steven, Groudine Mark, Bender M A, Palis James, Bulger Michael
Departments of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Box 703, 601 Elmwood Ave, Rochester, NY14642, USA.
Blood. 2009 Oct 15;114(16):3479-88. doi: 10.1182/blood-2009-03-210690. Epub 2009 Aug 18.
Active gene promoters are associated with covalent histone modifications, such as hyperacetylation, which can modulate chromatin structure and stabilize binding of transcription factors that recognize these modifications. At the beta-globin locus and several other loci, however, histone hyperacetylation extends beyond the promoter, over tens of kilobases; we term such patterns of histone modifications "hyperacetylated domains." Little is known of either the mechanism by which these domains form or their function. Here, we show that domain formation within the murine beta-globin locus occurs before either high-level gene expression or erythroid commitment. Analysis of beta-globin alleles harboring deletions of promoters or the locus control region demonstrates that these sequences are not required for domain formation, suggesting the existence of additional regulatory sequences within the locus. Deletion of embryonic globin gene promoters, however, resulted in the formation of a hyperacetylated domain over these genes in definitive erythroid cells, where they are otherwise inactive. Finally, sequences within beta-globin domains exhibit hyperacetylation in a context-dependent manner, and domains are maintained when transcriptional elongation is inhibited. These data narrow the range of possible mechanisms by which hyperacetylated domains form.
活跃的基因启动子与共价组蛋白修饰相关，例如组蛋白高度乙酰化，这种修饰可调节染色质结构并稳定识别这些修饰的转录因子的结合。然而，在β-珠蛋白基因座和其他几个基因座中，组蛋白高度乙酰化不仅局限于启动子区域，而是延伸数十千碱基；我们将这种组蛋白修饰模式称为“高度乙酰化结构域”。对于这些结构域的形成机制及其功能，我们知之甚少。在此，我们表明小鼠β-珠蛋白基因座内的结构域形成发生在高水平基因表达或红细胞定向分化之前。对缺失启动子或基因座控制区的β-珠蛋白等位基因的分析表明，这些序列对于结构域形成并非必需，这表明该基因座内存在其他调控序列。然而，在定型红细胞中，缺失胚胎珠蛋白基因启动子会导致这些基因上形成一个高度乙酰化结构域，而在其他情况下这些基因是不活跃的。最后，β-珠蛋白结构域内的序列以依赖于上下文的方式呈现高度乙酰化，并且当转录延伸受到抑制时结构域会得以维持。这些数据缩小了高度乙酰化结构域形成的可能机制范围。
