Cell Cycle
cell cycle
How polymer-loop-extruding motors shape chromosomes
Chromosomes are extremely long, active polymers that are spatially organized across multiple scales to promote cellular functions, such as gene transcription and genetic inheritance. During each cell cycle, chromosomes are dramatically compacted as cells divide and dynamically reorganized into less compact, spatiotemporally patterned structures after cell division. These activities are facilitated by DNA/chromatin-binding protein motors called SMC complexes. Each of these motors can perform a unique activity known as “loop extrusion,” in which the motor binds the DNA/chromatin polymer, reels in the polymer fiber, and extrudes it as a loop. Using simulations and theory, I show how loop-extruding motors can collectively compact and spatially organize chromosomes in different scenarios. First, I show that loop-extruding complexes can generate sufficient compaction for cell division, provided that loop-extrusion satisfies stringent physical requirements. Second, while loop-extrusion alone does not uniquely spatially pattern the genome, interactions between SMC complexes and protein “boundary elements” can generate patterns that emerge in the genome after cell division. Intriguingly, these “boundary elements” are not necessarily stationary, which can generate a variety of patterns in the neighborhood of transcriptionally active genes. These predictions, along with supporting experiments, show how SMC complexes and other molecular machinery, such as RNA polymerase, can spatially organize the genome. More generally, this work demonstrates both the versatility of the loop extrusion mechanism for chromosome functional organization and how seemingly subtle microscopic effects can emerge in the spatiotemporal structure of nonequilibrium polymers.
Building a synthetic cell: Understanding the clock design and function
Clock networks containing the same central architectures may vary drastically in their potential to oscillate, raising the question of what controls robustness, one of the essential functions of an oscillator. We computationally generate an atlas of oscillators and found that, while core topologies are critical for oscillations, local structures substantially modulate the degree of robustness. Strikingly, two local structures, incoherent and coherent inputs, can modify a core topology to promote and attenuate its robustness, additively. The findings underscore the importance of local modifications to the performance of the whole network. It may explain why auxiliary structures not required for oscillations are evolutionary conserved. We also extend this computational framework to search hidden network motifs for other clock functions, such as tunability that relates to the capabilities of a clock to adjust timing to external cues. Experimentally, we developed an artificial cell system in water-in-oil microemulsions, within which we reconstitute mitotic cell cycles that can perform self-sustained oscillations for 30 to 40 cycles over multiple days. The oscillation profiles, such as period, amplitude, and shape, can be quantitatively varied with the concentrations of clock regulators, energy levels, droplet sizes, and circuit design. Such innate flexibility makes it crucial to studying clock functions of tunability and stochasticity at the single-cell level. Combined with a pressure-driven multi-channel tuning setup and long-term time-lapse fluorescence microscopy, this system enables a high-throughput exploration in multi-dimension continuous parameter space and single-cell analysis of the clock dynamics and functions. We integrate this experimental platform with mathematical modeling to elucidate the topology-function relation of biological clocks. With FRET and optogenetics, we also investigate spatiotemporal cell-cycle dynamics in both homogeneous and heterogeneous microenvironments by reconstructing subcellular compartments.
Untitled Seminar
Measuring transcription at a single gene copy reveals hidden drivers of bacterial individuality
Single-cell measurements of mRNA copy numbers inform our understanding of stochastic gene expression, but these measurements coarse-grain over the individual copies of the gene, where transcription and its regulation take place stochastically. We recently combined single-molecule quantification of mRNA and gene loci to measure the transcriptional activity of an endogenous gene in individual Escherichia coli bacteria. When interpreted using a theoretical model for mRNA dynamics, the single-cell data allowed us to obtain the probabilistic rates of promoter switching, transcription initiation and elongation, mRNA release and degradation. Unexpectedly, we found that gene activity can be strongly coupled to the transcriptional state of another copy of the same gene present in the cell, and to the event of gene replication during the bacterial cell cycle. These gene-copy and cell-cycle correlations demonstrate the limits of mapping whole-cell mRNA numbers to the underlying stochastic gene activity and highlight the contribution of previously hidden variables to the observed population heterogeneity.
G1 sizer coordinates cell size and cell cycle in mammalian stem cells
Mass measurements during lymphocytic leukemia cell polyploidization decouple cell cycle and cell size dependent growth
Excess histone3 is a Chk1 inhibitor that controls embryonic cell cycle progression
Bridging integrator 1 (BIN1) isoforms expression in oligodendrocytes and their putative role in cell cycle regulation in sporadic Alzheimer’s disease
FENS Forum 2024
Neuropilin-mediated Sema 3 signaling is crucial for chick spinal cord neuroprogenitor cells to exit the cell cycle and protect early-born neurons from apoptosis
FENS Forum 2024