Biology subjects

Tabatabaee, S.

Publications and source records attributed to Tabatabaee, S..

6 recordsLinked to original sources

bioRxiv2026

Enhancer Tuning by Sequence-Specific Repressors

Enhancers integrate combinatorial inputs from sequence-specific transcription factors (TFs) and their activity must be calibrated to achieve precise spatiotemporal control of transcript dosage. Here we demonstrate that the sequence-specific repressors SNAI1 and SNAI2 (i.e. SNAIL and SLUG) quantitatively tune enhancer activity. In human neural crest cells, SNAI1/2 occupy a subset of active enhancers, where their depletion increases H3K27ac, chromatin accessibility, and enhancer regulatory potential. Changes in SNAI1/2 binding motifs contribute to enhancer divergence between human and chimpanzee, suggesting an evolutionary role for the repressor-mediated tuning. Single-molecule chromatin profiling using Deaminase-Assisted Fiber-seq (DAF-seq) reveals that individual enhancers toggle between an ensemble of open and nucleosome-dense chromatin states. While transcriptional activators increase the fraction of the open states, SNAI1/2 shift the equilibrium toward nucleosome-occupied states. This impedes binding of activator TFs, without fully repressing the enhancer. We propose that SNAI1/2 function as a molecular dimmer switch, modulating nucleosome dynamics to calibrate enhancer output.

molecular biology↗

bioRxiv2025

Xenophagocytosis blockade enhances interspecies chimerism

Organ shortage remains a major challenge in transplantation medicine. Interspecies blastocyst complementation is a promising approach to generate human organs in livestock hosts. However, getting xenogeneic donor cells to engraft and expand at early stages remains challenging. Here we identify an innate immune barrier, wherein host macrophages selectively recognize and eliminate viable xenogeneic donor cells. These events represent a form of phagoptosis and highlight a xenogeneic clearance process that we term xenophagocytosis. We identify the mechanism by which host macrophages selectively phagocytize xenogeneic donor cells: xenogeneic cells display elevated phosphatidylserine, an "eat-me" signal recognized by host macrophages through phagocytic receptor Axl. Xenophagocytosis blockade improves both rat and human donor chimerism in mouse embryos, indicating a conserved mechanism. These findings reveal potential mechanisms by which innate immune cells eliminate xenogeneic cells in early embryogenesis to preserve species integrity and offer improved strategies for generating human organs in livestock.

immunology↗

bioRxiv2024

Organ injury accelerates stem cell differentiation by modulating a fate-transducing lateral inhibition circuit

To rebuild tissue form and function, injured organs accelerate the differentiation of replacement stem cell progeny. Here we demonstrate that injury-induced factors open the throttle on faster differentiation by streamlining the archetypal signaling circuit that patterns cell fates. During normal turnover of the adult Drosophila intestine, fates are patterned by a conserved lateral inhibition circuit: In stem cell pairs, mutual activation of Notch receptor by Delta ligand feeds back to create opposing states of high Notch/low Delta and low Notch/high Delta; cells terminally differentiate once their Notch activity exceeds a fate-deciding threshold. After feeding flies a gut-damaging toxin, we perform in vivo imaging of real-time intestinal repair and trace Notch reporter dynamics in single cells. We find that tissue damage causes the speed of Notch signal activation to accelerate dramatically; faster activation expedites terminal differentiation by propelling cells past the critical Notch threshold more quickly. Combining single-cell analyses with dynamical modeling, we show that faster activation results from aberrant elevation of Delta ligand due to loss of time-delaying circuit feedback. Injury abolishes feedback via a cytokine-JAK-STAT relay from damaged cells to stem cells, causing stem cells to deactivate the Notch co-repressor that normally turns off Delta. Thus, organ injury unmasks latent plasticity in Notch-Delta lateral inhibition to propel the differentiation of new replacement cells. By unifying temporal and spatial fate control in a single, adaptable signaling circuit, organs tune stem cell dynamics to meet environmental challenges.

developmental biology↗

bioRxiv2024

Transfer learning reveals sequence determinants of the quantitative response to transcription factor dosage

Deep learning approaches have made significant advances in predicting cell type-specific chromatin patterns from the identity and arrangement of transcription factor (TF) binding motifs. However, most models have been applied in unperturbed contexts, precluding a predictive understanding of how chromatin state responds to TF perturbation. Here, we used transfer learning to train and interpret deep learning models that use DNA sequence to predict, with accuracy approaching experimental reproducibility, how the concentration of two dosage-sensitive TFs (TWIST1, SOX9) affects regulatory element (RE) chromatin accessibility in facial progenitor cells. High-affinity motifs that allow for heterotypic TF co-binding and are concentrated at the center of REs buffer against quantitative changes in TF dosage and strongly predict unperturbed accessibility. In contrast, motifs with low-affinity or homotypic binding distributed throughout REs lead to sensitive responses with minimal contributions to unperturbed accessibility. Both buffering and sensitizing features show signatures of purifying selection. We validated these predictive sequence features using reporter assays and showed that a biophysical model of TF-nucleosome competition can explain the sensitizing effect of low-affinity motifs. Our approach of combining transfer learning and quantitative measurements of the chromatin response to TF dosage therefore represents a powerful method to reveal additional layers of the cis-regulatory code.

genomics↗

bioRxiv2023

Robust trigger wave speed in Xenopus cytoplasmic extracts

Self-regenerating trigger waves can spread rapidly through the crowded cytoplasm without diminishing in amplitude or speed, providing consistent, reliable, long-range communication. The macromolecular concentration of the cytoplasm varies in response to physiological and environmental fluctuations, raising the question of how or if trigger waves can robustly operate in the face of such fluctuations. Using Xenopus extracts, we found that mitotic and apoptotic trigger wave speeds are remarkably invariant. We derived a model that accounts for this robustness and for the eventual slowing at extremely high and low cytoplasmic concentrations. The model implies that the positive and negative effects of cytoplasmic concentration (increased reactant concentration vs. increased viscosity) are nearly precisely balanced. Accordingly, artificially maintaining a constant cytoplasmic viscosity during dilution abrogates this robustness. The robustness in trigger wave speeds may contribute to the reliability of the extremely rapid embryonic cell cycle.

biophysics↗

bioRxiv2021

The critical role of spiny stellate cells in seizure onset based on dynamic analysis of a neural mass model

Growing evidence suggests that excitatory neurons in the brain play a significant role in seizure generation. Nonetheless, spiny stellate cells are cortical excitatory non-pyramidal neurons in the brain, which their basic role in seizure occurrence is not well understood. In the present research, we study the critical role of spiny stellate cells or the excitatory interneurons (EI), for the first time, in epileptic seizure generation using an extended neural mass model inspired by Liu and Wang model in 2017. Applying bifurcation analysis on this modified model, we investigated the rich dynamics corresponding to the epileptic seizure onset and transition between interictal and ictal states caused by EI connectivity to other cell types. Our results indicate that the transition between interictal and ictal states (preictal signal) corresponds to a supercritical Hopf bifurcation, and thus, the extended model suggests that before seizure onset, the amplitude and frequency of neural activities gradually increase. Moreover, we showed that 1) the altered function of GABAergic and glutamatergic receptors of EI can cause seizure, and 2) the pathway between the thalamic relay nucleus and EI facilitates the transition from interictal to the ictal activity by decreasing the preictal period. Thereafter, we considered both sensory and cortical periodic inputs to study model responses to various harmonic stimulations. Bifurcation analysis of the model, in this case, suggests that the initial state of the model might be the main cause for the transition between interictal and ictal states as the stimulus frequency changes. The extended thalamocortical model shows also that the amplitude jump phenomenon and nonlinear resonance behavior result from the preictal state of the modified model. These results can be considered as a step forward to a deeper understanding of the mechanisms underlying the transition from normal activities to epileptic activities.

neuroscience↗