Current Opinion in Systems Biology最新文献

To reliably form and maintain structures with specific functions, many multicellular systems evolved to leverage the interplay between biochemical signaling, mechanics, and morphology.

We review mechanochemical feedback loops in cases where cell–cell contact-based Notch signaling drives fate decisions, and the corresponding differentiation process leads to contact remodeling. We compare different mechanisms for initial symmetry breaking and subsequent pattern refinement, as well as discuss how patterning outcomes depend on the relationship between biochemical and mechanical timescales.

We conclude with an overview of new approaches, including the study of synthetic circuits, and give an outlook on future experimental and theoretical developments toward dissecting and harnessing mechanochemical feedback.

The central nervous system develops from a pool of neural progenitors which, depending on their location and time of division, generate cells committed to differentiate into specific kinds of neurons or glia. In the last decades, the developmental neurobiology field has made important progress in understanding neural cell-type specification: key patterning mechanisms were discovered, the different waves of neurogenesis described, and the dynamics of cortical stratification elucidated. However, only recently, with the advent of single-cell genomics and organoid culturing methods, we were able to measure the transcriptional signatures of individual progenitors systematically and flexibly perturb human development. Together these fine-grained readouts and perturbation possibilities have allowed comparing neural differentiation between species and dissecting the relationship between progenitors' phenotype and fate commitment. This review summarizes recent in vivo and in vitro studies that have contributed to our understanding of temporal progression and coordination of neuronal cell specification across mammals.

Models of transcriptional regulation that assume equilibrium binding of transcription factors have been less successful at predicting gene expression from sequence in eukaryotes than in bacteria. This could be due to the non-equilibrium nature of eukaryotic regulation. Unfortunately, the space of possible non-equilibrium mechanisms is vast and predominantly uninteresting. The key question is therefore how this space can be navigated efficiently, to focus on mechanisms and models that are biologically relevant. In this review, we advocate for the normative role of theory—theory that prescribes rather than just describes—in providing such a focus. Theory should expand its remit beyond inferring mechanistic models from data, towards identifying non-equilibrium gene regulatory schemes that may have been evolutionarily selected, despite their energy consumption, because they are precise, reliable, fast, or otherwise outperform regulation at equilibrium. We illustrate our reasoning by toy examples for which we provide simulation code.

The physics of critical points lies behind the organization of various complex systems, from molecules to ecosystems. Several functional benefits emerge when operating at the edge of a critical point, at criticality, potentially explaining the optimality of biological function. Here, we propose that introducing the concept of criticality in developmental biology may explain remarkable features of embryonic development, such as collective behavior and fitness. Recent interdisciplinary studies approached embryonic processes with statistical physics frameworks and revealed that biochemical and biomechanical processes of embryonic development resemble critical phenomena. We discuss those processes, including gene expression, cell differentiation, and tissue mechanics, and challenge if criticality has a beneficial function during embryonic organization.

The binding of transcription factors (TFs) via their DNA binding domain at gene promoters or enhancers is part of a multi-step process that leads to transcription activation in eukaryotes. The kinetic on- and off-rates of different TF states are governed by a complex interplay of factors that involve chromatin organization on the level of individual nucleosome positions up to actively transcribed chromatin subcompartments on the mesoscale. Furthermore, not only the TF DNA binding domain but also the activation domain affect TF assembly on chromatin. Here, we summarize recent findings on the interplay between TF binding, chromatin organization, and gene activation to highlight features that need to be considered for constructing quantitative models of eukaryotic gene regulation.

Decades of in vitro biochemical reconstitution, genetics and structural biology studies have established a vast knowledge base on the molecular mechanisms of chromatin regulation and transcription. A remaining challenge is to understand how these intricate biochemical systems operate in the context of the 3D genome organization and in the crowded and compartmentalized nuclear milieu. Here we review recent progress in this area based on high-resolution imaging approaches.

Mammalian development is characterized with transitions from homogeneous populations of precursor to heterogeneous population of specified cells. We review here the main dynamical mechanisms through which such transitions are conceptualized, and discuss that the differentiation timing, robust cell-type proportions and recovery upon perturbation are emergent property of proliferating and communicating cell populations. We argue that studying developmental systems using transitions in collective system states is necessary to describe observed experimental features, and propose additionally the basis of a novel analytical method to deduce the relationship between single-cell dynamics and the collective, symmetry-broken states in cellular populations.

Eukaryotes and bacteria have evolved entirely different mechanisms to cope with the problem of how to reconcile regulatory specificity in transcription, the recognition of specific DNA sequences by transcriptional activators, with speed, the ability to quickly respond to environmental change. It is argued here that eukaryotes enhance the specificity of activator–promoter recognition via ATP-dependent chromatin remodeling, whereas bacteria employ allosteric effectors to control specific activator–DNA binding reactions.