Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.
Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.
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DOI：
10.7554/elife.21926
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发表时间：
2017-03-23
期刊：
影响因子：
7.7
通讯作者：
Spivakov M
中科院分区：
文献类型：
--
作者：
Freire-Pritchett P;Schoenfelder S;Várnai C;Wingett SW;Cairns J;Collier AJ;García-Vílchez R;Furlan-Magaril M;Osborne CS;Fraser P;Rugg-Gunn PJ;Spivakov M
远程顺式调控元件如增强子通过参与DNA环与目标启动子的相互作用来协调细胞特异性转录程序。在谱系承诺过程中，破译启动子连接和顺式调控元件活性之间的相互作用对于理解发育转录控制至关重要。在这里，我们使用启动子捕获Hi-C生成一个高分辨率的染色体相互作用图谱，涉及人类多能性和谱系承诺细胞中约22,000个基因启动子，鉴定已知和预测的增强子元件的假定靶基因。我们揭示了谱系承诺的顺式调控接触的广泛动态，包括启动子相互作用的获得和损失。这种空间重新布线优先发生在顺式调控元件活性的预测变化中，并与靶基因表达的变化有关。我们的研究结果为人类多能细胞谱系承诺过程中启动子相互作用组动力学提供了一个全局和综合的观点。事实上，人体的每个细胞都含有相同的DNA，这些DNA编码了数千个基因。这些基因的活动在不同类型的细胞和不同的时间点上是不同的。因此，我们的DNA包含一系列复杂的分子开关，这些开关指示基因在正确的时间和正确的细胞中打开和关闭。这些分子开关，被称为调控元件，通常离它们控制的基因很远，这使得很难找出哪个开关控制哪个基因。DNA由称为碱基的几种不同的构建块组成，这些碱基的顺序编码有关基因的特定信息。每个人类细胞都含有大约两米长的DNA，这些DNA在细胞核中高度折叠。这种三维折叠使得DNA线上相隔很远的区域能够物理地相互接触。为了到达它们控制的基因，调控元件在DNA上形成环，这几乎是不可能单从碱基序列来预测的。绘制这些环的位置可以揭示我们DNA中隐藏的电路，并帮助我们了解调控元件中不需要的变化（突变）是如何导致疾病的。Freire-Pritchett、Schoenfelder等人着手揭示，当干细胞特化为未成熟的脑细胞时，基因及其调控元件之间的环是如何变化的。实验表明，在干细胞分化成脑细胞后，DNA环的模式发生了广泛的改变，也就是说，一些环丢失了，新的环形成了。此外，监管元素本身经常在“开”和“关”状态之间切换。这两个过程往往同时发生，因此在开关被激活的同时形成了新的回路。Freire-Pritchett、Schoenfelder等人也表明，单个基因通常与许多不同的调控元件有关。下一步是了解这些多重连接如何协同工作以协调基因活动，以及这些信息是否可以用于控制干细胞的特化。这一认识可能会导致以干细胞为基础的中风、帕金森病和其他疾病治疗的发展。DOI: http://dx.doi.org/10.7554/eLife.21926.002
Long-range cis-regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of cis-regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We reveal extensive dynamics of cis-regulatory contacts upon lineage commitment, including the acquisition and loss of promoter interactions. This spatial rewiring occurs preferentially with predicted changes in the activity of cis-regulatory elements and is associated with changes in target gene expression. Our results provide a global and integrated view of promoter interactome dynamics during lineage commitment of human pluripotent cells. DOI: http://dx.doi.org/10.7554/eLife.21926.001 Virtually every cell in the body contains the same set of DNA, which encodes thousands of genes. The activities of these genes vary between different types of cells and at different points in time. As a result, our DNA contains a complex array of molecular switches that instruct genes to switch on and off at the right time and in the right cells. These molecular switches, termed regulatory elements, are often a long way away from the genes that they control, and this can make it difficult to find out which switch controls which genes. DNA is made up of several different building blocks known as bases and the order of these bases encodes specific information about the gene. Every human cell contains approximately two meters of DNA, which is highly folded in the cell nucleus. This three-dimensional folding allows regions that are far apart on the DNA thread to physically contact each other. To reach the genes they control, regulatory elements form loops on the DNA that are near-impossible to predict from looking at the sequence of bases alone. Mapping the locations of these loops can reveal the hidden circuitry within our DNA and help us to understand how unwanted changes (mutations) within regulatory elements may cause disease. Freire-Pritchett, Schoenfelder et al. set out to reveal how loops between genes and their regulatory elements change as the stem cells specialise into immature brain cells. The experiments show that the pattern of DNA loops is extensively altered after the stem cells specialise into brain cells, that is, some loops are lost and new ones form. Furthermore, the regulatory elements themselves were often toggled between “on” and “off” states. These two processes tend to occur together, so that new loops are formed at the same time as the switch is activated. Freire-Pritchett, Schoenfelder et al. also show that individual genes are often connected to many different regulatory elements. The next step is to understand how these multiple connections work together to coordinate gene activity, and whether this information could be used to control how stem cells specialise. This knowledge may lead to the development of stem cell-based therapies for stroke, Parkinson’s disease and other conditions. DOI: http://dx.doi.org/10.7554/eLife.21926.002