stochastic mrna synthesis in mammalian cells随机mrna在哺乳动物细胞合成.pdfVIP

PLoS BIOLOGY Stochastic mRNA Synthesis in Mammalian Cells 1,2* 1 1 2 2* Arjun Raj , Charles S. Peskin , Daniel Tranchina , Diana Y. Vargas , Sanjay Tyagi 1 Courant Institute of Mathematical Sciences, New York University, New York, New York, United States of America, 2 Department of Molecular Genetics, Public Health Research Institute, Newark, New Jersey, United States of America Individual cells in genetically homogeneous populations have been found to express different numbers of molecules of specific proteins. We investigated the origins of these variations in mammalian cells by counting individual molecules of mRNA produced from a reporter gene that was stably integrated into the cell’s genome. We found that there are massive variations in the number of mRNA molecules present in each cell. These variations occur because mRNAs are synthesized in short but intense bursts of transcription beginning when the gene transitions from an inactive to an active state and ending when they transition back to the inactive state. We show that these transitions are intrinsically random and not due to global, extrinsic factors such as the levels of transcriptional activators. Moreover, the gene activation causes burst-like expression of all genes within a wider genomic locus. We further found that bursts are also exhibited in the synthesis of natural genes. The bursts of mRNA expression can be buffered at the protein level by slow protein degradation rates. A stochastic model of gene activation and inactivation was developed to explain the statistical properties of the bursts. The model showed that increasing the level of transcription factors increases the average size of the bursts rather than their frequency. These results demonstrate that gene expression in mammalian cells is subject to large, intrinsically