Divergent expression of paralogous genes by modification of shared enhancer activity through a promoter-proximal silencer.
Divergent expression of paralogous genes by modification of shared enhancer activity through a promoter-proximal silencer.
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DOI：
10.1016/j.cub.2022.06.069
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发表时间：
2022-08-22
期刊：
影响因子：
9.2
通讯作者：
Mann, Richard S.
中科院分区：
文献类型：
--
作者：
Loker, Ryan;Mann, Richard S.
基因及其相关顺式调控元件或增强子的复制是基因组进化和生物复杂性的关键因素。此外，许多旁系同源物，特别是串联重复，在共享增强子的控制下被固定很长一段时间。然而，在大多数情况下，基因表达和功能在复制后出现分歧的机制尚不清楚。在这里，我们剖析了果蝇翅膀发育过程中旁系同源 nubbin/pdm2 基因的调控和功能。我们证明这些旁系同源物在翼中发挥冗余作用，并且它们的表达依赖于单个共享翼增强子。然而，这两个基因对该增强子的反应能力有所不同，nub 在所有翼祖细胞中都有反应，而 pdm2 仅在一小部分细胞中有反应。这种分歧是 pdm2 启动子上 pdm2 特异性沉默元件的结果，该元件接收来自转录因子 Rotund 的抑制输入。通过该沉默子的抑制也依赖于 nub，当 nub 表达受到干扰并发生功能补偿时，pdm2 能够充分响应翼增强子。因此，共享增强子下游的表达分歧是由于沉默一个旁系同源物的启动子而产生的。 Loker 和 Mann 表明，果蝇中两个密切相关的旁系同源物 nub 和 pdm2 在翅膀发育中功能冗余，尽管它们在翼盘中受到相同增强子的调节，但由于翼盘通过其启动子对 pdm2 进行特异性抑制，因此它们具有不同的表达模式。
Duplication of genes and their associated cis-regulatory elements, or enhancers, is a key contributor to genome evolution and biological complexity. Moreover, many paralogs, particularly tandem duplicates, are fixed for long periods of time under the control of shared enhancers. However, in most cases the mechanism by which gene expression and function diverge following duplication is not known. Here we dissect the regulation and function of the paralogous nubbin/pdm2 genes during wing development in Drosophila melanogaster. We show that these paralogs play a redundant role in the wing and that their expression relies on a single shared wing enhancer. However, the two genes differ in their ability to respond to this enhancer, with nub responding in all wing progenitor cells and pdm2 only in a small subset. This divergence is a result of a pdm2-specific silencer element at the pdm2 promoter that receives repressive input from the transcription factor Rotund. Repression through this silencer also depends on nub, allowing pdm2 to fully respond to the wing enhancer when nub expression is perturbed and functional compensation to occur. Thus, expression divergence downstream of a shared enhancer arises as a consequence of silencing the promoter of one paralog. Loker and Mann show that two closely related paralogs in Drosophila, nub and pdm2, function redundantly in wing development and, although they are regulated by the same enhancer in wing discs, they have distinct expression patterns due to wing disc-specific repression of pdm2 through its promoter.
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