CTCF通过β-珠蛋白基因座中细胞类型特异性染色体组构介导的转录调控
CTCF-mediated transcriptional regulation through cell type-specific chromosome organization in the β-globin locus
摘要：
尽管染色质在哺乳动物基因调控中具有潜在的作用，但其在活细胞核小体水平之外的结构景观的基本原理仍然很不清楚。我们研究了包含β-珠蛋白基因的人类11号染色体1 Mbp区域的三维折叠，通过将由染色体构象捕获（3C）全面确定的绝缘子蛋白CTCF的成环相互作用整合到染色质的聚合物模型中。我们发现在红系细胞中CTCF介导的细胞类型特异性相互作用被组织成有利于已知在体内发生在β-珠蛋白基因座控制区（LCR）和基因之间的接触。在这些细胞中，模拟的β-珠蛋白结构域折叠成球状，LCR和活性珠蛋白基因位于外周。相比之下，在非红系细胞中，小球不太紧凑，很少但占主导地位的CTCF相互作用驱动基因远离LCR。这导致接触频率的降低，根据染色质的硬度和基因的精确定位，接触频率可以超过1000倍。我们的研究结果表明，CTCF接触的合奏功能影响控制元件和靶基因之间的空间距离，有助于转录所需的染色体组织。
英文摘要：
The principles underlying the architectural landscape of chromatin beyond the nucleosome level in living cells remains largely unknown despite its potential to play a role in mammalian gene regulation. We investigated the 3-dimensional folding of a 1 Mbp region of human chromosome 11 containing the β-globin genes by integrating looping interactions of the insulator protein CTCF determined comprehensively by chromosome conformation capture (3C) into a polymer model of chromatin. We find that CTCF-mediated cell type specific interactions in erythroid cells are organized to favor contacts known to occur in vivo between the β-globin locus control region (LCR) and genes. In these cells, the modeled β-globin domain folds into a globule with the LCR and the active globin genes on the periphery. By contrast, in non-erythroid cells, the globule is less compact with few but dominant CTCF interactions driving the genes away from the LCR. This leads to a decrease in contact frequencies that can exceed 1000-fold depending on the stiffness of the chromatin and the exact positioning of the genes. Our findings show that an ensemble of CTCF contacts functionally affects spatial distances between control elements and target genes contributing to chromosomal organization required for transcription.
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