Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Headington, Oxford, OX3 9DS, United Kingdom.
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21771-6. doi: 10.1073/pnas.0909331106. Epub 2009 Dec 3.
It is well established that all of the cis-acting sequences required for fully regulated human alpha-globin expression are contained within a region of approximately 120 kb of conserved synteny. Here, we show that activation of this cluster in erythroid cells dramatically affects expression of apparently unrelated and noncontiguous genes in the 500 kb surrounding this domain, including a gene (NME4) located 300 kb from the alpha-globin cluster. Changes in NME4 expression are mediated by physical cis-interactions between this gene and the alpha-globin regulatory elements. Polymorphic structural variation within the globin cluster, altering the number of alpha-globin genes, affects the pattern of NME4 expression by altering the competition for the shared alpha-globin regulatory elements. These findings challenge the concept that the genome is organized into discrete, insulated regulatory domains. In addition, this work has important implications for our understanding of genome evolution, the interpretation of genome-wide expression, expression-quantitative trait loci, and copy number variant analyses.
已经证实，完全调节人α-珠蛋白表达所需的所有顺式作用序列都包含在大约 120kb 的保守同线区内。在这里，我们表明，该簇在红细胞中的激活会显著影响该区域周围 500kb 内明显不相关和不连续基因的表达，包括一个位于 300kb 外的α-珠蛋白簇的基因（NME4）。NME4 表达的变化是由该基因与α-珠蛋白调节元件之间的物理顺式相互作用介导的。珠蛋白簇内的多态结构变异，改变了α-珠蛋白基因的数量，通过改变共享α-珠蛋白调节元件的竞争，影响 NME4 的表达模式。这些发现挑战了基因组组织成离散、隔离的调节域的概念。此外，这项工作对我们理解基因组进化、全基因组表达的解释、表达数量性状基因座和拷贝数变异分析具有重要意义。
