A coarse-grained resource allocation model of carbon and nitrogen metabolism in unicellular microbes.

Coarse-grained resource allocation models (C-GRAMs) are simple mathematical models of cell physiology, where large components of the macromolecular composition are abstracted into single entities. The dynamics and steady-state behaviour of such models provides insights on optimal allocation of cellular resources and have explained experimentally observed cellular growth laws, but current models do not account for the uptake of compound sources of carbon and nitrogen. Here, we formulate a C-GRAM with nitrogen and carbon pathways converging on biomass production, with parametrizations accounting for respirofermentative and purely respiratory growth.

Genetic effects on molecular network states explain complex traits.

The complexity of many cellular and organismal traits results from the integration of genetic and environmental factors via molecular networks. Network structure and effect propagation are best understood at the level of functional modules, but so far, no concept has been established to include the global network state. Here, we show when and how genetic perturbations lead to molecular changes that are confined to small parts of a network versus when they lead to modulation of network states.

Modelling capture efficiency of single-cell RNA-sequencing data improves inference of transcriptome-wide burst kinetics.

Motivation: Gene expression is characterized by stochastic bursts of transcription that occur at brief and random periods of promoter activity. The kinetics of gene expression burstiness differs across the genome and is dependent on the promoter sequence, among other factors. Single-cell RNA sequencing (scRNA-seq) has made it possible to quantify the cell-to-cell variability in transcription at a global genome-wide level.

Fission yeast obeys a linear size law under nutrient titration.

Steady-state cell size and geometry depend on growth conditions. Here, we use an experimental setup based on continuous culture and single-cell imaging to study how cell volume, length, width and surface-to-volume ratio vary across a range of growth conditions including nitrogen and carbon titration, the choice of nitrogen source, and translation inhibition. Overall, we find cell geometry is not fully determined by growth rate and depends on the specific mode of growth rate modulation.

Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin.

Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states.

Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells.

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear.

Data-driven spatio-temporal modelling of glioblastoma.

Mathematical oncology provides unique and invaluable insights into tumour growth on both the microscopic and macroscopic levels. This review presents state-of-the-art modelling techniques and focuses on their role in understanding glioblastoma, a malignant form of brain cancer. For each approach, we summarize the scope, drawbacks and assets.

Injury primes mutation-bearing astrocytes for dedifferentiation in later life.

Despite their latent neurogenic potential, most normal parenchymal astrocytes fail to dedifferentiate to neural stem cells in response to injury. In contrast, aberrant lineage plasticity is a hallmark of gliomas, and this suggests that tumor suppressors may constrain astrocyte dedifferentiation. Here, we show that p53, one of the most commonly inactivated tumor suppressors in glioma, is a gatekeeper of astrocyte fate.

Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters.

Innate immune responses rely on inducible gene expression programmes which, in contrast to steady-state transcription, are highly dependent on cohesin. Here we address transcriptional parameters underlying this cohesin-dependence by single-molecule RNA-FISH and single-cell RNA-sequencing. We show that inducible innate immune genes are regulated predominantly by an increase in the probability of active transcription, and that probabilities of enhancer and promoter transcription are coordinated.

Growth-rate-dependent and nutrient-specific gene expression resource allocation in fission yeast.

Cellular resources are limited and their relative allocation to gene expression programmes determines physiological states and global properties such as the growth rate. Here, we determined the importance of the growth rate in explaining relative changes in protein and mRNA levels in the simple eukaryote grown on non-limiting nitrogen sources. Although expression of half of fission yeast genes was significantly correlated with the growth rate, this came alongside wide-spread nutrient-specific regulation.

R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.

Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events.

The white matter is a pro-differentiative niche for glioblastoma.

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency.

A bacterial size law revealed by a coarse-grained model of cell physiology.

Universal observations in Biology are sometimes described as "laws". In E. coli, experimental studies performed over the past six decades have revealed major growth laws relating ribosomal mass fraction and cell size to the growth rate.

Size-Dependent Increase in RNA Polymerase II Initiation Rates Mediates Gene Expression Scaling with Cell Size.

Cell size varies during the cell cycle and in response to external stimuli. This requires the tight coordination, or "scaling," of mRNA and protein quantities with the cell volume in order to maintain biomolecule concentrations and cell density. Evidence in cell populations and single cells indicates that scaling relies on the coordination of mRNA transcription rates with cell size.

bayNorm: Bayesian gene expression recovery, imputation and normalization for single-cell RNA-sequencing data.

Motivation: Normalization of single-cell RNA-sequencing (scRNA-seq) data is a prerequisite to their interpretation. The marked technical variability, high amounts of missing observations and batch effect typical of scRNA-seq datasets make this task particularly challenging. There is a need for an efficient and unified approach for normalization, imputation and batch effect correction.

Single-cell imaging and RNA sequencing reveal patterns of gene expression heterogeneity during fission yeast growth and adaptation.

Phenotypic cell-to-cell variability is a fundamental determinant of microbial fitness that contributes to stress adaptation and drug resistance. Gene expression heterogeneity underpins this variability but is challenging to study genome-wide. Here we examine the transcriptomes of >2,000 single fission yeast cells exposed to various environmental conditions by combining imaging, single-cell RNA sequencing and Bayesian true count recovery.

Condensin controls cellular RNA levels through the accurate segregation of chromosomes instead of directly regulating transcription.

Condensins are genome organisers that shape chromosomes and promote their accurate transmission. Several studies have also implicated condensins in gene expression, although any mechanisms have remained enigmatic. Here, we report on the role of condensin in gene expression in fission and budding yeasts.

Long noncoding RNA repertoire and targeting by nuclear exosome, cytoplasmic exonuclease, and RNAi in fission yeast.

Long noncoding RNAs (lncRNAs), which are longer than 200 nucleotides but often unstable, contribute a substantial and diverse portion to pervasive noncoding transcriptomes. Most lncRNAs are poorly annotated and understood, although several play important roles in gene regulation and diseases. Here we systematically uncover and analyze lncRNAs in Based on RNA-seq data from twelve RNA-processing mutants and nine physiological conditions, we identify 5775 novel lncRNAs, nearly 4× the previously annotated lncRNAs.

Division rate, cell size and proteome allocation: impact on gene expression noise and implications for the dynamics of genetic circuits.

The cell division rate, size and gene expression programmes change in response to external conditions. These global changes impact on average concentrations of biomolecule and their variability or noise. Gene expression is inherently stochastic, and noise levels of individual proteins depend on synthesis and degradation rates as well as on cell-cycle dynamics.

The Wound Microenvironment Reprograms Schwann Cells to Invasive Mesenchymal-like Cells to Drive Peripheral Nerve Regeneration.

Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves.