Stochasticity of cellular differentiation

RATIONALE: Cardiac muscle cells are terminally differentiated after birth and must beat continually throughout one's lifetime. This mechanical process is driven by the sliding of actin-based thin filaments along myosin-based thick filaments, organized within sarcomeres. Despite costly energetic demand, the half-life of the proteins that comprise the cardiac thick filaments is ~10 days, with individual molecules being replaced stochastically, by unknown mechanisms. OBJECTIVES: To allow for the stochastic replacement of molecules, we hypothesized that the structure of thick filaments must be highly dynamic in vivo...

BACKGROUND: Ischemic stroke, the most common stroke type, has threatened human life and health. Currently, intravenous thrombolysis and endovascular thrombectomy are the mainstream treatment methods, but they may cause cerebral ischemia-reperfusion injury (CIRI), which aggravates brain injury. Consequently, it is worthwhile to start with a study of CIRI mechanism to identify better prevention and treatment methods. Applying single-cell RNA sequencing (scRNA-seq) technology to further understand the biological functions of various cell types in CIRI will facilitate the intervention of CIRI...

Calcium (Ca2+ ) imaging reveals a variety of correlated firing in cultures of dissociated hippocampal neurons, pinpointing the non-synaptic paracrine release of glutamate as a possible mediator for such firing patterns, although the biophysical underpinnings remain unknown. An intriguing possibility is that extracellular glutamate could bind metabotropic receptors linked with inositol trisphosphate (IP3 ) mediated release of Ca2+ from the endoplasmic reticulum of individual neurons, thereby modulating neural activity in combination with sarco/endoplasmic reticulum Ca2+ transport ATPase (SERCA) and voltage-gated Ca2+ channels (VGCC)...

Oestrogen receptor expression in breast cancer (BC) cells is a marker of high cellular differentiation and allows the identification of two BC groups (ER-positive and ER-negative) that, although not completely homogeneous, differ in biological characteristics, clinical behaviour, and therapeutic options. The study, based on three publicly available EWAS (Epigenetic Wide Association Study) datasets, focuses on the comparison between these two groups of breast cancer using an epimutation score. The score is calculated not only based on the presence of the epimutation, but also on the deviation amplitude of the methylation outlier value...

In 2016, Hao and Friedman developed a deterministic model of Alzheimer's disease progression using a system of partial differential equations. This model describes the general behavior of the disease, however, it does not incorporate the molecular and cellular stochasticity intrinsic to the underlying disease processes. Here we extend the Hao and Friedman model by modeling each event in disease progression as a stochastic Markov process. This model identifies stochasticity in disease progression, as well as changes to the mean dynamics of key agents...

MOTIVATION: One central goal of systems biology is to infer biochemical regulations from large-scale OMICS data. Many aspects of cellular physiology and organismal phenotypes can be understood as results of metabolic interaction network dynamics. Previously, we have proposed a convenient mathematical method which addresses this problem using metabolomics data for the inverse calculation of biochemical Jacobian matrices revealing regulatory checkpoints of biochemical regulations. The proposed algorithms for this inference are limited by two issues: they rely on structural network information that needs to be assembled manually, and they are numerically unstable due to ill-conditioned regression problems for large-scale metabolic networks...

Different ion channels present in the osteoblast regulate the cellular functions including bio-mineralization, a process that is a highly stochastic event. Cellular events and molecular signaling involved in such process is poorly understood. Here we demonstrate that TRPV4, a mechanosensitive ion channel is endogenously present in an osteoblast cell line (MC3T3-E1) and in primary osteoblasts. Pharmacological activation of TRPV4 enhanced intracellular Ca2+ -level, expression of osteoblast-specific genes and caused increased bio-mineralization...

Variability of gene expression due to stochasticity of transcription or variation of extrinsic signals, termed biological noise, is a potential driving force of cellular differentiation. Utilizing single-cell RNA-sequencing, we develop VarID2 for the quantification of biological noise at single-cell resolution. VarID2 reveals enhanced nuclear versus cytoplasmic noise, and distinct regulatory modes stratified by correlation between noise, expression, and chromatin accessibility. Noise levels are minimal in murine hematopoietic stem cells (HSCs) and increase during differentiation and ageing...

The transcription of DNA by RNA polymerase occurs as a discontinuous process described as transcriptional bursting. This bursting behavior is observed across species and has been quantified using various stochastic modeling approaches. There is a large body of evidence that suggests the bursts are actively modulated by transcriptional machinery and play a role in regulating developmental processes. Under a commonly used two-state model of transcription, various enhancer-, promoter- and chromatin microenvironment-associated features are found to differentially influence the size and frequency of bursting events - key parameters of the two-state model...

BACKGROUND: Bioinformatics capability to analyze spatio-temporal dynamics of gene expression is essential in understanding animal development. Animal cells are spatially organized as functional tissues where cellular gene expression data contain information that governs morphogenesis during the developmental process. Although several computational tissue reconstruction methods using transcriptomics data have been proposed, those methods have been ineffective in arranging cells in their correct positions in tissues or organs unless spatial information is explicitly provided...

Gene expression stochasticity is inherent in the functional properties and evolution of biological systems, creating non-genetic cellular individuality and influencing multiple processes, including differentiation and stress responses. In a distinct form of non-transcriptional noise, we find that interactions of the yeast translation machinery with the GCN4 mRNA 5'UTR, which underpins starvation-induced regulation of this transcriptional activator gene, manifest stochastic variation across cellular populations...

Curli amyloid fibers are a major constituent of the extracellular biofilm matrix formed by bacteria of the Enterobacteriaceae family. Within Escherichia coli biofilms, curli gene expression is limited to a subpopulation of bacteria, leading to heterogeneity of extracellular matrix synthesis. Here we show that bimodal activation of curli gene expression also occurs in well-mixed planktonic cultures of E. coli, resulting in all-or-none stochastic differentiation into distinct subpopulations of curli-positive and curli-negative cells at the entry into the stationary phase of growth...

This research illustrates that complex dynamics of gene products enable the creation of any prescribed cellular differentiation patterns. These complex dynamics can take the form of chaotic, stochastic, or noisy chaotic dynamics. Based on this outcome and previous research, it is established that a generic open chemical reactor can generate an exceptionally large number of different cellular patterns. The mechanism of pattern generation is robust under perturbations and it is based on a combination of Turing's machines, Turing instability and L...

The standard diagnosis of prostate cancer is accomplished by the identification of cytomorphological deviations in biopsied tissues while immunohistochemistry is used to resolve the equivocal cases. Accumulating evidence favors the concept that epithelial-to-mesenchymal transition (EMT) is a stochastic process composed of multiple intermediate states instead of a single binary switch. Despite its significant role in promoting cancer aggressiveness, the current tissue-based risk stratification tools do not include any of the EMT phenotypes as a metric...

Nongenetic heterogeneity is key to cellular decisions, as even genetically identical cells respond in very different ways to the same external stimulus, e.g., during cell differentiation or therapeutic treatment of disease. Strong heterogeneity is typically already observed at the level of signaling pathways that are the first sensors of external inputs and transmit information to the nucleus where decisions are made. Since heterogeneity arises from random fluctuations of cellular components, mathematical models are required to fully describe the phenomenon and to understand the dynamics of heterogeneous cell populations...

In the last two decades, an increasing number of bacterial species have been recognized that are able to generate a phenotypically diverse population that shares an identical genotype. This ability is dependent on a complex genetic regulatory network that includes cellular and environmental signals, as well as stochastic elements. Among Bacilli, a broadly distributed family of Rap (Response-regulator aspartyl phosphate) phosphatases is known to modulate the function of the main phenotypic heterogeneity regulators by controlling their phosphorylation...

Multicellular patterning of stem-cell-derived tissue models is commonly achieved via self-organizing activities triggered by exogenous morphogenetic stimuli. However, such tissue models are prone to stochastic behavior, limiting the reproducibility of cellular composition and forming non-physiological architectures. To enhance multicellular patterning in stem cell-derived tissues, a method for creating complex tissue microenvironments endowed with programmable multimodal mechano-chemical cues, including conjugated peptides, proteins, morphogens, and Young's moduli defined over a range of stiffnesses is developed...

In the last decade, several experimental studies have shown how chromatin modifications (histone modifications and DNA methylation) and their effect on DNA compaction have a critical effect on cellular reprogramming, i.e., the conversion of differentiated cells to a pluripotent state. In this paper, we compare three reprogramming approaches that have been considered in the literature: (a) prefixed overexpression of transcription factors (TFs) alone (Oct4), (b) prefixed overexpression of Oct4 and DNA methylation "eraser" TET, and (c) prefixed overexpression of Oct4 and H3K9me3 eraser JMJD2...

In Bacillus subtilis, master regulator Spo0A controls several cell-differentiation pathways. Under moderate starvation, phosphorylated Spo0A (Spo0A~P) induces biofilm formation by indirectly activating genes controlling matrix production in a subpopulation of cells via an SinI-SinR-SlrR network. Under severe starvation, Spo0A~P induces sporulation by directly and indirectly regulating sporulation gene expression. However, what determines the heterogeneity of individual cell fates is not fully understood. In particular, it is still unclear why, despite being controlled by a single master regulator, biofilm matrix production and sporulation seem mutually exclusive on a single-cell level...

The Cancer Stem Model allows for a dynamical description of cancer colonies which accounts for the existence of different families of cells, namely stem cells, highly proliferating and quasi-immortal, and differentiated cells, both undergoing cellular processes under numerous activated pathways. In the present work, we investigate a dynamical model numerically, as a system of coupled differential equations, and include a plasticity mechanism, of differentiated cells turning into a stem state if the stem concentration drops low...