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    Rando, O. J. ; Paulsson, J. Noisy silencing of chromatin. Developmental Cell 2006, 11, 134-6.Abstract
    Chromatin-based repression is a major mechanism for epigenetically heritable variation. Work in the July 21 issue of Molecular Cell quantitatively examines transcriptional silencing in individual yeast cells, demonstrating locus-specific effects and finding that different silencing mutants exhibit qualitatively distinct single-cell defects.
    Pedraza, J. M. ; Paulsson, J. Effects of molecular memory and bursting on fluctuations in gene expression. Science 2008, 319, 339-43.Abstract
    Many cellular components are present in such low numbers per cell that random births and deaths of individual molecules can cause substantial "noise" in concentrations. But biochemical events do not necessarily occur in single steps of individual molecules. Some processes are greatly randomized when synthesis or degradation occurs in large bursts of many molecules during a short time interval. Conversely, each birth or death of a macromolecule could involve several small steps, creating a memory between individual events. We present a generalized theory for stochastic gene expression, formulating the variance in protein abundance in terms of the randomness of the individual gene expression events. We show that common types of molecular mechanisms can produce gestation and senescence periods that reduce noise without requiring higher abundances, shorter lifetimes, or any concentration-dependent control loops. We also show that most single-cell experimental methods cannot distinguish between qualitatively different stochastic principles, although this in turn makes such methods better suited for identifying which components introduce fluctuations. Characterizing the random events that give rise to noise in concentrations instead requires dynamic measurements with single-molecule resolution.
    Paulsson, J. ; Chattoraj, D. K. Origin inactivation in bacterial DNA replication control. Molecular Microbiology 2006, 61, 9-15.Abstract
    Initiation of DNA replication is a highly regulated process in all organisms. Proteins that are required to recruit DNA polymerase - initiator proteins - are often used to regulate the timing or frequency of initiation in the cell cycle by limiting either their own synthesis or availability. Studies of the Escherichia coli chromosome and of bacterial plasmids with iterated initiator binding sites (iterons) have revealed that, in addition to initiator limitation, replication origin inactivation is used to prevent replication that is untimely or excessive. Our recent studies of plasmid P1 revealed that this additional mode of control becomes a requirement when initiator availability is limited only by autoregulation. Thus, although initiator limitation appears to be a well-conserved and central mode of replication control, optimal replication might require additional control mechanisms. This review gives examples of how the multiple mechanisms can act synergistically, antagonistically or be partially redundant to guarantee low frequency events. The lessons learned are likely to help understand many other regulatory systems in the bacterial cell.
    Bar-Even, A. ; Paulsson, J. ; Maheshri, N. ; Carmi, M. ; O'Shea, E. ; Pilpel, Y. ; Barkai, N. Noise in protein expression scales with natural protein abundance. Nature Genetics 2006, 38, 636-43.Abstract
    Noise in gene expression is generated at multiple levels, such as transcription and translation, chromatin remodeling and pathway-specific regulation. Studies of individual promoters have suggested different dominating noise sources, raising the question of whether a general trend exists across a large number of genes and conditions. We examined the variation in the expression levels of 43 Saccharomyces cerevisiae proteins, in cells grown under 11 experimental conditions. For all classes of genes and under all conditions, the expression variance was approximately proportional to the mean; the same scaling was observed at steady state and during the transient responses to the perturbations. Theoretical analysis suggests that this scaling behavior reflects variability in mRNA copy number, resulting from random 'birth and death' of mRNA molecules or from promoter fluctuations. Deviation of coexpressed genes from this general trend, including high noise in stress-related genes and low noise in proteasomal genes, may indicate fluctuations in pathway-specific regulators or a differential activation pattern of the underlying gene promoters.

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