Transcriptome Analysis in Yeast Reveals the Externality of Position Effects
The activity of a gene newly integrated into a chromosome depends on the genomic context of the integration site. This “position effect” has been widely reported, although the other side of the coin, that is, how integration affects the local chromosomal environment, has remained largely unexplored, as have the mechanism and phenotypic consequences of this “externality” of the position effect. Here, we examined the transcriptome profiles of approximately 250 Saccharomyces cerevisiae strains, each with GFP integrated into a different locus of the wild-type strain. We found that in genomic regions enriched in essential genes, GFP expression tended to be lower, and the genes near the integration site tended to show greater expression reduction. Further joint analysis with public genome-wide histone modification profiles indicated that this effect was associated with H3K4me2. More importantly, we found that changes in the expression of neighboring genes, but not GFP expression, significantly altered the cellular growth rate. As a result, genomic loci that showed high GFP expression immediately after integration were associated with growth disadvantages caused by elevated expression of neighboring genes, ultimately leading to a low total yield of GFP in the long run. Our results were consistent with competition for transcriptional resources among neighboring genes and revealed a previously unappreciated facet of position effects. This study highlights the impact of position effects on the fate of exogenous gene integration and has significant implications for biological engineering and the pathology of viral integration into the host genome.
期刊:
Molecular Biology and Evolution
2021
作者:
Xiaoshu Chen,Zheng Hu,Zifeng Cui,Wenbing Jiang,Xiujuan Cai,Wenjun Shi,Xin Zhang,Waifang Cao,Zhenzhen Zhou,Shuyun Deng,Qian Gui
DOI:10.1093/molbev/msab104
Bidirectional Genetic Control of Phenotypic Heterogeneity and Its Implication for Cancer Drug Resistance
Negative genetic regulators of phenotypic heterogeneity, or phenotypic capacitors/stabilizers, elevate population average fitness by limiting deviation from the optimal phenotype and increase the efficacy of natural selection by enhancing the phenotypic differences among genotypes. Stabilizers can presumably be switched off to release phenotypic heterogeneity in the face of extreme or fluctuating environments to ensure population survival. This task could, however, also be achieved by positive genetic regulators of phenotypic heterogeneity, or “phenotypic diversifiers,” as shown by recently reported evidence that a bacterial divisome factor enhances antibiotic resistance. We hypothesized that such active creation of phenotypic heterogeneity by diversifiers, which is functionally independent of stabilizers, is more common than previously recognized. Using morphological phenotypic data from 4,718 single-gene knockout strains of Saccharomyces cerevisiae, we systematically identified 324 stabilizers and 160 diversifiers and constructed a bipartite network between these genes and the morphological traits they control. Further analyses showed that, compared with stabilizers, diversifiers tended to be weaker and more promiscuous (regulating more traits) regulators targeting traits unrelated to fitness. Moreover, there is a general division of labor between stabilizers and diversifiers. Finally, by incorporating NCI-60 human cancer cell line anticancer drug screening data, we found that human one-to-one orthologs of yeast diversifiers/stabilizers likely regulate the anticancer drug resistance of human cancer cell lines, suggesting that these orthologs are potential targets for auxiliary treatments. Our study therefore highlights stabilizers and diversifiers as the genetic regulators for the bidirectional control of phenotypic heterogeneity as well as their distinct evolutionary roles and functional independence.
期刊:
Molecular Biology and Evolution
2020
作者:
Jian-Rong Yang,Xiaoshu Chen,Gongwang Yu,Wenjun Shi,Xiaoyu Zhang,Ning Mo
DOI:10.1093/molbev/msaa332
