Department of Biology, William Paterson University, Wayne, New Jersey, USA.
Department of Chemistry, William Paterson University, Wayne, New Jersey, USA.
mSphere. 2019 Mar 13;4(2):e00063-19. doi: 10.1128/mSphere.00063-19.
Balancing gene expression is a fundamental challenge of all cell types. To properly regulate transcription on a genome-wide level, there are myriad mechanisms employed by the cell. One layer to this regulation is through spatial positioning, with particular chromosomal loci exerting an influence on transcription throughout a region. Many coregulated gene families utilize spatial positioning to coordinate transcription, with functionally related genes clustering together which can allow coordinated expression via adjacent gene coregulation. The mechanisms underlying this process have not been elucidated, though there are many coregulated gene families that exhibit this genomic distribution. In the present study, we tested for a role for the enhancer-promoter (EP) hypothesis, which demonstrates that regulatory elements can exert transcriptional effects over a broad distance, in coordinating transcriptional coregulation using budding yeast, We empirically validated the EP model, finding that the genomic distance a promoter can affect varies by locus, which can profoundly affect levels of transcription, phenotype, and the extent of transcriptional disruption throughout a genomic region. Using the nitrogen metabolism, ribosomal protein, toxin response, and heat shock gene families as our test case, we report functionally clustered genes localize to genomic loci that are more conducive to transcriptional regulation at a distance compared to the unpaired members of the same families. Furthermore, we report that the coregulation of functional clusters is dependent, in part, on chromatin maintenance and remodeling, providing one mechanism underlying adjacent gene coregulation. The two-dimensional, physical positioning of genes along a chromosome can impact proper transcriptional regulation throughout a genomic region. The transcription of neighboring genes is correlated in a genome-wide manner, which is a characteristic of eukaryotes. Many coregulated gene families can be found clustered with another member of the same set-which can result in adjacent gene coregulation of the pair. Due to the myriad gene families that exhibit a nonrandom genomic distribution, there are likely multiple mechanisms working in concert to properly regulate transcriptional coordination of functionally clustered genes. In this study, we utilized budding yeast in an attempt to elucidate mechanisms that underlie this coregulation: testing and empirically validating the enhancer-promoter hypothesis in this species and reporting that functionally related genes cluster to genomic regions that are more conducive to transcriptional regulation at a distance. These clusters rely, in part, on chromatin maintenance and remodelers to maintain proper transcriptional coordination. Our work provides insight into the mechanisms underlying adjacent gene coregulation.
平衡基因表达是所有细胞类型的基本挑战。为了在全基因组水平上正确调节转录，细胞采用了无数种机制。这种调节的一个层面是通过空间定位，特定的染色体位置对整个区域的转录产生影响。许多共同调控的基因家族利用空间定位来协调转录，功能相关的基因聚集在一起，通过相邻基因的共同调控可以实现协调表达。尽管有许多共同调控的基因家族表现出这种基因组分布，但这个过程的机制尚未阐明。在本研究中，我们通过 budding yeast 检验了增强子-启动子（EP）假说在协调转录中的作用，该假说表明调节元件可以在广泛的距离上发挥转录效应。我们通过实验验证了 EP 模型，发现启动子可以影响的基因组距离因位置而异，这会极大地影响转录水平、表型以及整个基因组区域转录中断的程度。我们使用氮代谢、核糖体蛋白、毒素反应和热休克基因家族作为我们的测试案例，报告功能聚类的基因定位于基因组位置，与同一家族的非配对成员相比，这些位置更有利于远距离转录调控。此外，我们还报告说，功能聚类的共调控部分依赖于染色质的维持和重塑，这为相邻基因共调控提供了一种机制。基因沿着染色体的二维物理定位会影响整个基因组区域的正确转录调控。相邻基因的转录在全基因组范围内相关，这是真核生物的一个特征。许多共同调控的基因家族可以与同一组的另一个成员聚类——这可能导致对该对基因的相邻基因共调控。由于存在许多表现出非随机基因组分布的基因家族，因此可能有多种机制协同作用以正确调节功能聚类基因的转录协调。在这项研究中，我们利用 budding yeast 试图阐明这种共调控的机制：在该物种中测试和实证验证增强子-启动子假说，并报告功能相关的基因聚类到基因组区域，这些区域更有利于远距离转录调控。这些聚类部分依赖于染色质维持和重塑剂来维持适当的转录协调。我们的工作为相邻基因共调控的机制提供了深入的了解。
