Biology subjects

Binshtok, U.

Publications and source records attributed to Binshtok, U..

3 recordsLinked to original sources

bioRxiv2025

A model of transcriptional bursting dynamics based on coupling between chromatin and enhancer states

In recent years, it has become evident that transcription is not always a continuous process. Rather, many genes exhibit bursting behavior characterized by discrete periods of transcriptional activity and inactivity. While transcriptional bursting has been broadly observed across different organisms, from bacteria to mammals, we lack a mechanistic understanding of the molecular events that regulate this widespread process. Specifically, how the expression of a bursty gene is quantitatively determined by different molecular factors such as the concentration of transcription factors (TF) and architecture of the enhancers is not well understood. Here, we introduce a model based on the interplay between chromatin state and TF binding in order to describe bursting dynamics. We leverage the widespread Monod-Wyman-Changeux two-state model to predict the dependence of transcriptional bursting dynamics on TF concentration, binding affinity, and number of TF binding sites. We use the model to qualitatively reproduce the behavior of bursting dynamics observed in the C. elegans gonad. Overall, we provide a tractable model for transcriptional bursting that offers mechanistic insights into the factors regulating transcriptional bursting and generates experimentally testable predictions capable of uncovering the molecular basis of this widespread process.

biophysics↗

bioRxiv2022

Cis-inhibition suppresses basal Notch signalling during sensory organ precursor selection

The emergence of the sensory organ precursor (SOP) from the proneural equivalence group in Drosophila melanogaster is a paradigm for studying single cell fate specification through the process of lateral inhibition. Classical lateral inhibition models describing this selection process are based on a transcriptional feedback mechanism where inhibitory signals between neighbouring cells, mediated by Notch pathway, are coupled to an intracellular circuit regulating the expression of the Notch ligand Delta (Dl). It was previously shown that in addition to its ability to trans-activate Notch in neighbouring cells, Dl can also cis-inhibit Notch in the same cell. However, it remains unclear what role does cis-inhibition play during SOP selection, and how it contributes to the selection of only one SOP. Here we address these questions using the unexpected observation that the mammalian ligand Delta-like 1 (Dll1) can trans-activate but not cis-inhibit Notch in Drosophila. We develop a mathematical model for SOP selection, termed the two-channel SOP (TCS) model, where Dl activity, but not its expression, is regulated by two channels associated with the two E3 ubiquitin ligases Neuralized (Neur) and Mindbomb1 (Mib1). While the Neur-dependent channel is regulated by Notch signalling, the Mib1-dependent channel is not, leading to tissue-wide basal inhibitory activity. We show theoretically and experimentally that cis-inhibition is required for suppressing Mib1-dependent basal Notch activity. Thus, our results highlight the trade-off between basal Notch activity and cis-inhibition as a mechanism for singling out an SOP from the proneural equivalence group.

developmental biology↗

bioRxiv2020

Dynamic spatiotemporal coordination of neural stem cell fate decisions through local feedback in the adult vertebrate brain

Neural stem cell (NSC) populations persist in the adult vertebrate brain over a life time, and their homeostasis is controlled at the population level. The nature and properties of these coordination mechanisms remain unknown. Here we combine dynamic imaging of entire NSC populations in their in vivo niche over weeks, pharmacological manipulations, mathematical modeling and spatial statistics, and demonstrate that NSCs use spatiotemporally resolved local feedbacks to coordinate their decision to divide. These involve a Notch-mediated inhibition from transient neural progenitors, and a dispersion effect from dividing NSCs themselves, exerted with a delay of 9-12 days. Simulations from a stochastic NSC lattice model capturing these interactions demonstrate that they are linked by lineage progression and control the spatiotemporal distribution of output neurons. These results highlight how local and temporally delayed interactions occurring between brain germinal cells generate self-propagating dynamics that maintain NSC population homeostasis with specific spatiotemporal correlations.

neuroscience↗