Current Opinion in Systems Biology最新文献

The binding of transcription factors (TFs) via their DNA binding domain at gene promoters or enhancers is part of a multi-step process that leads to transcription activation in eukaryotes. The kinetic on- and off-rates of different TF states are governed by a complex interplay of factors that involve chromatin organization on the level of individual nucleosome positions up to actively transcribed chromatin subcompartments on the mesoscale. Furthermore, not only the TF DNA binding domain but also the activation domain affect TF assembly on chromatin. Here, we summarize recent findings on the interplay between TF binding, chromatin organization, and gene activation to highlight features that need to be considered for constructing quantitative models of eukaryotic gene regulation.

Decades of in vitro biochemical reconstitution, genetics and structural biology studies have established a vast knowledge base on the molecular mechanisms of chromatin regulation and transcription. A remaining challenge is to understand how these intricate biochemical systems operate in the context of the 3D genome organization and in the crowded and compartmentalized nuclear milieu. Here we review recent progress in this area based on high-resolution imaging approaches.

Mammalian development is characterized with transitions from homogeneous populations of precursor to heterogeneous population of specified cells. We review here the main dynamical mechanisms through which such transitions are conceptualized, and discuss that the differentiation timing, robust cell-type proportions and recovery upon perturbation are emergent property of proliferating and communicating cell populations. We argue that studying developmental systems using transitions in collective system states is necessary to describe observed experimental features, and propose additionally the basis of a novel analytical method to deduce the relationship between single-cell dynamics and the collective, symmetry-broken states in cellular populations.

Eukaryotes and bacteria have evolved entirely different mechanisms to cope with the problem of how to reconcile regulatory specificity in transcription, the recognition of specific DNA sequences by transcriptional activators, with speed, the ability to quickly respond to environmental change. It is argued here that eukaryotes enhance the specificity of activator–promoter recognition via ATP-dependent chromatin remodeling, whereas bacteria employ allosteric effectors to control specific activator–DNA binding reactions.

The text-book picture of a perfect, well organised metabolism with highly specific enzymes, is challenged by non-enzymatic reactions and promiscuous enzymes. This, so-called ‘underground metabolism’, is a special challenge for hyperthermophilic Archaea that thrive at temperatures above 80 °C and possess modified central metabolic pathways often with promiscuous enzymes. Hence, the question arises how extremely thermophilic Archaea can operate their unusual metabolism at temperatures where many pathway intermediates are unstable? We herein discuss current insights in the underground metabolism and metabolic thermoadaptation of (hyper)thermophilic Archaea. So far, only a few repair enzymes and salvaging pathways have been investigated in Archaea. Studies of the central carbohydrate metabolism indicate that a number of different strategies have evolved: 1) reduction of the concentration of unstable metabolites, 2) different pathway topologies are used with newly induced enzymes, and 3) damaged metabolites are removed via new metabolic pathways.

Synthetic biology modifies biological systems with the aim of creating new biological parts, devices, and even organisms. Systems biology deciphers the design principles of biological systems trying to derive the mathematical logic behind biological processes. Although different in their respective research approaches and questions, both disciplines are clearly interconnected. Without sufficient understanding of the biological system, synthetic biology studies cannot be properly designed and conducted. On the other hand, systems biology can profit from new biological systems generated by synthetic biology approaches, which can reveal important insights into cellular processes and allow a better understanding of the principles of life. In this article, we present state-of-the-art synthetic biology approaches that focus on the engineering of synthetic metabolism in microbial hosts and show how their implementation has led to new fundamental discoveries on enzyme reversibility, promiscuity, and “underground metabolism”. We further discuss how the combination of rational engineering and adaptive laboratory evolution has enabled the generation of microbes with a synthetic central metabolism, leading to completely new metabolic phenotypes. These organisms provide a great resource for future studies to deepen our systems-level understanding on the principles that govern metabolic networks and evolution.

While we have a solid understanding of the cell biological and biochemical control aspects of the eukaryotic cell growth and division process, much less is known about the metabolic and biosynthetic dynamics during the cell cycle. Here, we review recent discoveries made at the single-cell and population level that show that budding yeast (Saccharomyces cerevisiae) metabolism oscillates in synchrony with the cell cycle in actively dividing cells, as well as independently when the cell cycle is halted. In fact, emerging evidence suggests that the cell cycle-independent metabolic oscillations interact with elements of the cell cycle machinery via several possible mechanisms. Furthermore, recent reports indicate that different biosynthetic processes exhibit temporally changing activity patterns during the cell cycle. Thus, resources are drawn from primary metabolism in a dynamic manner, potentially giving rise to metabolic oscillations. Finally, we highlight work with mammalian cells indicating that similar metabolic dynamics might also exist in higher eukaryotes.