Lee Jongjoo, Krivega Ivan, Dale Ryan K, Dean Ann
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2017 Jun 20;19(12):2490-2502. doi: 10.1016/j.celrep.2017.05.072.
Lineage-specific transcription factors are critical for long-range enhancer interactions, but direct or indirect contributions of architectural proteins such as CCCTC-binding factor (CTCF) to enhancer function remain less clear. The LDB1 complex mediates enhancer-gene interactions at the β-globin locus through LDB1 self-interaction. We find that an LDB1-bound enhancer upstream of carbonic anhydrase 2 (Car2) activates its expression by interacting directly with CTCF at the gene promoter. Both LDB1 and CTCF are required for enhancer-Car2 looping, and the domain of LDB1 contacted by CTCF is necessary to rescue Car2 transcription in LDB1-deficient cells. Genome-wide studies and CRISPR/Cas9 genome editing indicate that LDB1-CTCF enhancer looping underlies activation of a substantial fraction of erythroid genes. Our results provide a mechanism by which long-range interactions of architectural protein CTCF can be tailored to achieve a tissue-restricted pattern of chromatin loops and gene expression.
谱系特异性转录因子对于远距离增强子相互作用至关重要，但诸如CCCTC结合因子（CTCF）等结构蛋白对增强子功能的直接或间接贡献仍不太清楚。LDB1复合物通过LDB1自身相互作用介导β-珠蛋白基因座处的增强子-基因相互作用。我们发现碳酸酐酶2（Car2）上游与LDB1结合的增强子通过在基因启动子处与CTCF直接相互作用来激活其表达。增强子与Car2的环化需要LDB1和CTCF，并且CTCF接触的LDB1结构域对于挽救LDB1缺陷细胞中的Car2转录是必需的。全基因组研究和CRISPR/Cas9基因组编辑表明，LDB1-CTCF增强子环化是很大一部分红系基因激活的基础。我们的结果提供了一种机制，通过该机制可以调整结构蛋白CTCF的远距离相互作用，以实现染色质环化和基因表达的组织限制性模式。
