)Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control
绝缘社区: 控制哺乳动物基因的结构和功能单位
Richard A. Young
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Understanding how tranional enhancers control over 20,000 protein-coding genes to maintain cell-type-specific gene expression programs in all human cells is a fundamental challenge in regulatory biology.
了解 基因转录调控增强子如何控制表达20000个蛋白编码基因的细胞类型特异性表达 是一个研究人类细胞基因表达调控的基本挑战。
Recent studies suggest that gene regulatory elements and their target genes generally occur within insulated neighborhoods, which are chromosomal loop structures formed by the interaction of two DNA sites bound by the CTCF protein and occupied by the cohesin complex.
最近的研究表明，基因调控单元及其靶标基因通常定位于同一绝缘社区内
；是染色体循环结构之间的相互作用形成的高级空间结构，染色体DNA受CTCF蛋白质和DNA被cohesin蛋白结合并形成高级空间结构。
Here, we review evidence that insulated neighborhoods provide for specific enhancer-gene interactions, are essential for both normal gene activation and repression, form a chromosome scaffold that is largely preserved throughout development, and are perturbed by genetic and epigenetic factors in disease.
我们提供的证据表明：绝缘社区包含特定增强子和基因序列的交互。在很大程度上是在发育特定过程形成一个染色体支架，对正常基因激活和阻遏调控至关重要，也是在疾病成因的遗传和表观遗传因素。
Insulated neighborhoodsare a powerful paradigm for gene control that provides new insights into development and disease.
绝缘社区是一个强大的基因控制模式，本文提供了新的见解和疾病发展。
Fig.1
The Enhancer-Gene-Specificity Conundrum
增强子和基因特异互作模型谜题
(A) Model of a genomic region encompassing an enhancer and two genes.
(A) 基因组区域的模型的包含一个增强子和两个基因。
The features that cause an enhancer to regulate only specific genes are still not fully understood, which we refer to as theenhancer-gene specificity conundrum.
这样的序列特性导致增强子如何只调节特定基因还没有完全理解，我们称之为“增强子和基因特异性难题”。
(B) Model of a genomic region encompassing an enhancer and two genes with the tranion factor CTCF bound in between.
(B) 基因组区域的模型包括一个增强器和两个基因的转录因子CTCF绑定。
CTCF is a component of enhancer-blocking insulators, but which CTCF-bound sites function as an insulator in vivo is still unclear.
CTCF 增强子阻遏调控绝缘体是一个组成部分，但CTCF互作位点作为绝缘体体内功能机制尚不清楚。
Fig. 2
Insulated Neighborhoods
绝缘社区
(A) Hierarchy of chromosome structures: chromosome territories, TADs, and insulated neighborhoods.
(A) 染色体结构层次: 染色体领土,TAD结构域，绝缘社区。
Anchor refers to the CTCF-bound site interacting with another CTCF-bound sites, both co-bound by a cohesin ring.
锚是指CTCF结合DNA位点与另一个CTCF结合DNA位点互作，并被cohesin蛋白锁定。
(B) Features of insulated neighborhoods in human embryonic stem cells (ESCs). (B) 人类胚胎干细胞(ESCs)绝缘社区的功能特征。
The values displayed for the size range and number of genes represent the middle 95% of the data range.
显示的值的大小范围和数量基因代表中间95%的数据范围。
(C) Evidence for insulation of insulated neighborhoods: 90% of enhancer-gene interactions occur within insulated neighborhoods in human ESCs.
(C) 绝缘社区阻遏基因表达的证据表明： 90%的增强子和基因的交互发生在人类的胚胎干细胞（ESCs）绝缘社区内。
(D) Evidence for insulation of insulated neighborhoods: deletion of insulated neighborhood anchors leads to gene misregulation.
(D) 绝缘社区阻遏基因表达的证据表明：删除绝缘锚蛋白 导致基因错误调控。
(E) Evidence for insulation of insulated neighborhoods: mutations of insulated neighborhood anchors in tumor cells lead to oncogene activation.
(E) 绝缘社区阻遏基因表达的证据表明：绝缘区的锚蛋白在肿瘤细胞的突变导致癌基因激活。
Fig.3
Insulated Neighborhoods in Development
发育生物学的“绝缘社区”情况
Cell-specific enhancer-gene interactions occur within insulated neighborhoods that are generally maintained in different cell types.
不同的细胞类型内 特异性增强子与基因交互发生在“绝缘社区”内。
Left side displays a linear model of a genomic region encompassing a gene associated with cell-type-specific enhancers, the right side displays the insulated neighborhood model of the locus.
左侧显示一个线性模型的基因组区域内 细胞类型特异的增强子包括一个相关联的基因的互作；右侧显示绝缘附近的轨迹模型。
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