Kassouf Mira T, Francis Helena S, Gosden Matthew, Suciu Maria C, Downes Damien J, Harrold Caroline, Larke Martin, Oudelaar Marieke, Cornell Lucy, Blayney Joseph, Telenius Jelena, Xella Barbara, Shen Yuki, Sousos Nikolaos, Sharpe Jacqueline A, Sloane-Stanley Jacqueline, Smith Andrew J H, Babbs Christian, Hughes Jim R, Higgs Douglas R
Gene Regulation Laboratory, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DS, Oxford, UK.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DS, Oxford, UK.
Nat Commun. 2025 Jan 25;16(1):1033. doi: 10.1038/s41467-025-56380-1.
Individual enhancers are defined as short genomic regulatory elements, bound by transcription factors, and able to activate cell-specific gene expression at a distance, in an orientation-independent manner. Within mammalian genomes, enhancer-like elements may be found individually or within clusters referred to as locus control regions or super-enhancers (SEs). While these behave similarly to individual enhancers with respect to cell specificity, distribution and distance, their orientation-dependence has not been formally tested. Here, using the α-globin locus as a model, we show that while an individual enhancer works in an orientation-independent manner, the direction of activity of a SE changes with its orientation. When the SE is inverted within its normal chromosomal context, expression of its normal targets, the α-globin genes, is severely reduced and the normally silent genes lying upstream of the α-globin locus are upregulated. These findings add to our understanding of enhancer-promoter specificity that precisely activate transcription.
单个增强子被定义为短的基因组调控元件，可被转录因子结合，并能够以方向独立的方式在远距离激活细胞特异性基因表达。在哺乳动物基因组中，增强子样元件可能单独存在，也可能存在于称为基因座控制区或超级增强子（SEs）的簇中。虽然这些元件在细胞特异性、分布和距离方面的行为与单个增强子相似，但其方向依赖性尚未得到正式测试。在这里，我们以α-珠蛋白基因座为模型，表明虽然单个增强子以方向独立的方式起作用，但SE的活性方向会随其方向而变化。当SE在其正常染色体背景下倒置时，其正常靶标α-珠蛋白基因的表达会严重降低，而位于α-珠蛋白基因座上游的正常沉默基因会被上调。这些发现加深了我们对精确激活转录的增强子-启动子特异性的理解。
