Systems biology of circadian rhythms: an outlook

The circadian system in higher organisms temporally orchestrates rhythmic changes in a vast number of genes and gene products in different organs. Complex interactions between these components, both within and among cells, ultimately lead to rhythmic behavior and physiology. Identifying the plethora of circadian targets and mapping their interactions with one another is therefore essential to comprehend the molecular mechanisms of circadian regulation. The emergence of new technology for unbiased identification of biomolecules and for mapping interactions at the genome-wide scale is offering powerful tools to decipher the regulatory networks underpinning circadian rhythms. In this review, the authors discuss the potential application of these genome-wide approaches in the study of circadian rhythms.     

Systems cell biology

Upon starvation, Grh1, a peripheral membrane protein located at endoplasmic reticulum (ER) exit sites and early Golgi in Saccharomyces cerevisiae under growth conditions, relocates to a compartment called compartment for unconventional protein secretion (CUPS). Here we report that CUPS lack Golgi enzymes, but contain the coat protein complex II (COPII) vesicle tethering protein Uso1 and the Golgi t-SNARE Sed5. Interestingly, CUPS biogenesis is independent of COPII- and COPI-mediated membrane transport. Pik1- and Sec7-mediated membrane export from the late Golgi is required for complete assembly of CUPS, and Vps34 is needed for their maintenance. CUPS formation is triggered by glucose, but not nitrogen starvation. Moreover, upon return to growth conditions, CUPS are absorbed into the ER, and not the vacuole. Altogether our findings indicate that CUPS are not specialized autophagosomes as suggested previously. We suggest that starvation triggers relocation of secretory and endosomal membranes, but not their enzymes, to generate CUPS to sort and secrete proteins that do not enter, or are not processed by enzymes of the ER–Golgi pathway of secretion.     

Systems chemical biology

The increasing availability of data related to genes, proteins and their modulation by small molecules has provided a vast amount of biological information leading to the emergence of systems biology and the broad use of simulation tools for data analysis. However, there is a critical need to develop cheminformatics tools that can integrate chemical knowledge with these biological databases and simulation approaches, with the goal of creating systems chemical biology.     

The cellular biology of megakaryocytes

Megakaryocytes show a pattern of cellular proliferation and maturation which is unique in mammalian biology. Cells mature to the point of cytoplasmic fragmentation in three major ploidy classes, 8n, 16n, and 32n and the three are fed from a precursor committed stem cell. Two-thirds of the cells belong in the 16n class, and approximately one-sixth in the 8n and 32n classes. The cytoplasm of cells in each ploidy class has a characteristic concentration of granules and demarcation membrane system which appears to be translated into the characteristic features of the platelet progeny from each class. These differ from normal young platelets. Megakaryocytes release fragments of cytoplasm into marrow sinusoids and these differ from platelets in that they do not have the peripheral microtubular bundle or sub-marginal dense tubular system. Transition from fragment to circulating platelet presumably takes place elsewhere in the circulation. With stimulation of platelet production, "stress" platelets are produced, from megakaryocytes which show changes with respect to content of polyribosomes, glycogen and membrane.     

Structural biology of cellular machines

Multi-component macromolecular machines contribute to all essential biological processes, from cell motility and signal transduction to information storage and processing. Structural analysis of assemblies at atomic resolution is emerging as the field of structural cell biology. Several recent studies, including those focused on the ribosome, the acrosomal bundle and bacterial flagella, have demonstrated the ability of a hybrid approach that combines imaging, crystallography and computational tools to generate testable atomic models of fundamental biological machines. A complete understanding of cellular and systems biology will require the detailed structural understanding of hundreds of biological machines. The realization of this goal demands a concerted effort to develop and apply new strategies for the systematic identification, isolation, structural characterization and mechanistic analysis of multi-component assemblies at all resolution ranges. The establishment of a database describing the structural and dynamic properties of protein assemblies will provide novel opportunities to define the molecular and atomic mechanisms controlling overall cell physiology.     

Systems biology of bacterial chemotaxis

Motile bacteria regulate chemotaxis through a highly conserved chemosensory signal-transduction system. System-wide analyses and mathematical modeling are facilitated by extensive experimental observations regarding bacterial chemotaxis proteins, including biochemical parameters, protein structures and protein-protein interaction maps. Thousands of signaling and regulatory chemotaxis proteins within a bacteria cell form a highly interconnected network through distinct protein-protein interactions. A bacterial cell is able to respond to multiple stimuli through a collection of chemoreceptors with different sensory modalities, which interact to affect the cooperativity and sensitivity of the chemotaxis response. The robustness or insensitivity of the chemotaxis system to perturbations in biochemical parameters is a product of the system's hierarchical network architecture.     

Systems biology of embryonic morphogens

A network of secreted proteins that interact with each other in the extracellular space regulates embryonic morphogenesis. Mathematical modeling offers an excellent opportunity to understand how morphogens signal and self-regenerate pattern.