Top(ological-operon) secret behind the long-range transcriptional coupling.
Top(ological-operon) secret behind the long-range transcriptional coupling.
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DOI：
10.1038/s41392-022-01195-5
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发表时间：
2022-10-15
影响因子：
39.3
通讯作者：
Lu, Huasong
中科院分区：
文献类型：
--
作者：
Zhang, Lei;Wu, Zhibing;Lu, Huasong
Levo 等人最近在《自然》杂志上发表的一项研究中。报道称，相距较远的旁系同源基因受到称为束缚元件的特殊 DNA 延伸的调节，这使得它们在果蝇胚胎发生过程中能够进行物理关联和相互依赖的转录耦合。 1 真核基因组通过多尺度结构的层次结构进行空间组织。 2, 3 越来越多的证据表明，高阶染色质组织的动态调节在机制上很有趣，更重要的是，具有生物学意义。例如，粘连蛋白复合物产生的环状结构有助于将分离的 DNA 元件束缚在物理上接近的位置，以实现远程基因调控。从功能上讲，染色质结构的正确组织在谱系规范和细胞分化等各种生物过程中起着至关重要的作用，这些结构的破坏可能导致发育障碍和人类疾病。 3 虽然通过环挤出机制形成的结构域已被广泛研究，以描述启动子-增强子通讯的关键事件，并为了解远距离调控元件如何作用于相应的个体基因以微调其表达提供基础，但过去对其他调控相互作用模式的研究相对较少。特别是，据报道，具有长距离连接的基因优先以共同调控的方式转录。 4 然而，共同调控基因的空间参与与其转录耦合之间的因果关系仍然存在争议。旁系同源物是位于不同基因组位置但在共同生物过程中发挥相互关联的作用的重复基因。 Levo 等人利用胚胎发育过程中重叠的表达模式。探索这些基因协调表达的机制原理。他们首先采用 Micro-C，这是一种基于 3C 的最先进方法，可在核小体分辨率下提供更精细的染色体组织，5 用于绘制早期果蝇胚胎中染色质折叠的图谱。该分析揭示了大量的远程焦点接触，其中大多数对应于由共享增强子共同调控的旁系同源物。因此，这些结果暗示，需要重新审视后生动物基因调控的传统观点，即单个基因通过其自身的调控元件独立控制，以阐明这些相互关联的旁系同源物的共同依赖性激活。
In a recent study published in Nature, Levo et al. reported that paralogous genes separated by long distances are regulated by specialized DNA stretches called tethering elements, which enable their physical associations and co-dependent transcriptional coupling during Drosophila embryogenesis. 1 The eukaryotic genome is spatially organized via a hierarchy of multi-scale structures. 2, 3 Accumulating evidence suggests that the dynamic regulation of higher-order chromatin organization is mechanistically interesting and, more importantly, biologically significant. For instance, loop-like structure generated by cohesin complex facilitates the tethering of separated DNA elements into physical proximity for long-range gene regulation. Functionally, the proper organization of chromatin architecture plays an essential role in various biological processes such as lineage specification and cell differentiation, and disruption of these structures can lead to developmental disorders and human diseases. 3 While the domain formation by loop extrusion mechanism has been extensively investigated to delineate the key events underlying promoter-enhancer communication and provide a foundation for understanding how distant regulatory elements act on corresponding individual genes to fine-tune their expression, other modes of regulatory interactions have been relatively understudied in the past. In particular, genes with long-range connectivity have been reported to be preferentially transcribed in a co-regulated manner. 4 Yet, the causal relationship between spatial engagement of co-regulated genes and their transcriptional coupling remains debatable.Paralogues are duplicated genes that reside at different genomic locations but play interconnected roles in a common biological process. Taking advantage of their overlapping expression pattern during embryonic development, Levo et al. explored the mechanistic principles underlying the coordinated expression of these genes. They first employed Micro-C, a stateof-art 3C-based method that provides finer-scale chromosome organization at nucleosome-resolution, 5 for mapping chromatin folding in early fly embryos. This analysis revealed a large number of long-range focal contacts, most of which correspond to paralogues that are co-regulated by shared enhancers. These results therefore hinted that the conventional view of metazoan gene regulation, which claims that individual genes are independently controlled via their own regulatory elements, needs to be revisited to elucidate the co-dependent activation of these interconnected paralogues.
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