Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA; Department of Neuroscience, Department of Systems Biology, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
Curr Biol. 2022 Aug 22;32(16):3545-3555.e4. doi: 10.1016/j.cub.2022.06.069. Epub 2022 Jul 18.
The 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.
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贡献因素。此外，许多同源基因，特别是串联重复基因，在共享增强子的控制下会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发生分歧的机制尚不清楚。在这里，我们在果蝇的翅膀发育过程中解析了同源基因 nubbin/pdm2 的调控和功能。我们发现这些同源基因在翅膀中发挥冗余作用，它们的表达依赖于一个单一的共享翅膀增强子。然而，这两个基因在对该增强子的反应能力上存在差异，nub 在所有翅膀祖细胞中表达，而 pdm2 仅在一小部分细胞中表达。这种差异是由于 pdm2 启动子上的 pdm2 特异性沉默元件造成的，该元件接收转录因子 Rotund 的抑制性输入。通过这个沉默元件的抑制也依赖于 nub，当 nub 的表达受到干扰时，pdm2 能够完全响应翅膀增强子，从而实现功能补偿。因此，共享增强子下游的表达差异是由于一个同源基因的启动子被沉默而产生的。
