A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis

ABSTRACT Cells do not make fate decisions independently. Arguably, every cell-fate decision occurs in response to environmental signals. In many cases, cell-cell communication alters the dynamics of the internal gene regulatory network of a cell to initiate cell-fate transitions, yet models rarely take this into account. Here, we have developed a multiscale perspective to study the granulocyte-monocyte versus megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network: a classical example of a bistable cell-fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell-fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell-fate decision-making system. This article has an associated ‘The people behind the papers’ interview.

insideOutside: an accessible algorithm for classifying interior and exterior points, with applications in embryology

A crucial aspect of embryology is relating the position of individual cells to the broader geometry of the embryo. A classic example can be seen in the first cell-fate decision of the mouse embryo, where interior cells become inner cell mass and exterior cells become trophectoderm. Advances in image acquisition and processing technology used by quantitative immunofluorescence have resulted in the production of embryo images with increasingly rich spatial information that demand accessible analytical methods. Here, we describe a simple mathematical framework and an unsupervised machine learning approach for classifying interior and exterior points of a three-dimensional point-cloud. We benchmark our method to demonstrate that it yields higher classification rates for pre-implantation mouse embryos and greater accuracy when challenged with local surface concavities. This method should prove useful to experimentalists within and beyond embryology, with broader applications in the biological and life sciences.

Trehalose pathway regulates filamentation response in Saccharomyces cerevisiae

In Saccharomyces cerevisae , the diploid cells undergo either pseudohyphal differentiation or sporulation in response to carbon and nitrogen source depletion. Distinct pathways are known to regulate the processes of filamentation and sporulation in response to nutritional stress. Here, we report the novel finding that the trehalose pathway which is essential for sporulation, is involved in pseudohyphae formation both via GPR1 as well as RAS2 mediated signaling. Our observations indicate that GPR1 is epistatic over TPS1 in signaling for filamentation. Further, we have demonstrated that the pseudohyphal defect of the ras2 mutant is overcome upon disruption of TPS2 . Thus, our results indicate that TPS1 and TPS2 may be involved in cell fate decision between meiosis and filamentation response under nutrient depleting conditions. Further, monitoring pseudohyphae formation under limiting glucose condition unravelled the possibility that TPS1 and TPS2 exert opposing effects to trigger filamentation response.

Interactions between Viral Regulatory Proteins Ensure an MOI-Independent Probability of Lysogeny during Infection by Bacteriophage P1

Phage P1 has been shown potentially to play an important role in disseminating antibiotic resistance among bacteria during lysogenization, as evidenced by the prevalence of P1 phage-like elements in animal and human pathogens. In contrast to phage λ, a cell fate decision-making paradigm, P1 lysogenization was shown to be independent of MOI.

Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.

A hydraulic instability drives the cell death decision in the nematode germline

Oocytes are large cells that develop into an embryo upon fertilization1. As interconnected germ cells mature into oocytes, some of them grow—typically at the expense of others that undergo cell death2–4. We present evidence that in the nematode Caenorhabditis elegans, this cell-fate decision is mechanical and related to tissue hydraulics. An analysis of germ cell volumes and material fluxes identifies a hydraulic instability that amplifies volume differences and causes some germ cells to grow and others to shrink, a phenomenon that is related to the two-balloon instability5. Shrinking germ cells are extruded and they die, as we demonstrate by artificially reducing germ cell volumes via thermoviscous pumping6. Our work reveals a hydraulic symmetry-breaking transition central to the decision between life and death in the nematode germline.

Insights into the molecular mechanisms of cell fate decision making processes from chromosome structural dynamics

Cell state transitions or cell fate decision making processes, such as cell development and cell pathological transformation, are believed to be determined by the regulatory network of genes, which intimately depend on the structures of chromosomes in the cell nucleus. The high temporal resolution picture of how chromosome reorganizes its 3D structure during the cell state transitions is the key to understanding the mechanisms of these fundamental cellular processes. However, this picture is still challenging to acquire at present. Here, we studied the chromosome structural dynamics during the cell state transitions among the pluripotent embryonic stem cell (ESC), the terminally differentiated normal cell and the cancer cell using landscape-switching model implemented in the molecular dynamics simulation. We considered up to 6 transitions, including differentiation, reprogramming, cancer formation and reversion. We found that the pathways can merge at certain stages during the transitions for the two processes having the same destination as the ESC or the normal cell. Before reaching the merging point, the two pathways are cell-type-specific. The chromosomes at the merging points show high structural similarity to the ones at the final cell states in terms of the contact maps, TADs and compartments. The post-merging processes correspond to the adaption of the chromosome global shape geometry through the chromosome compaction without significantly disrupting the contact formation. On the other hand, our detailed analysis showed no merging point for the two cancer formation processes initialized from the ESC and the normal cell, implying that cancer progression is a complex process and may be associated with multiple pathways. Our results draw a complete molecular picture of cell development and cancer at the dynamical chromosome structural level, and help our understanding of the molecular mechanisms of cell fate decision making processes.

Accessible chromatin reveals regulatory mechanisms underlying cell fate decisions during early embryogenesis

This study was conducted to investigate epigenetic landscape across multiple species and identify transcription factors (TFs) and their roles in controlling cell fate decision events during early embryogenesis. We made a comprehensively joint-research of chromatin accessibility of five species during embryogenesis by integration of ATAC-seq and RNA-seq datasets. Regulatory roles of candidate early embryonic TFs were investigated. Widespread accessible chromatin in early embryos overlapped with putative cis-regulatory sequences. Sets of cell-fate-determining TFs were identified. YOX1, a key cell cycle regulator, were found to homologous to clusters of TFs that are involved in neuron and epidermal cell-fate determination. Our research provides an intriguing insight into evolution of cell-fate decision during early embryogenesis among organisms.