Current Opinion in Cell Biology最新文献

Biologists have the capability to edit a genome at the nanometer scale and then observe whether or not the edit affects the structure of a developing organ or organism at the centimeter scale. Our understanding of the underlying mechanisms driving this emergent phenomenon from a multiscale perspective remains incomplete. This review focuses predominantly on recent experimental developments in uncovering the mechanical interplay between the chromatin and cell scale since mechanics plays a major role in determining nuclear, cellular, and tissue structure. Here, we discuss the generation and transmission of forces through the cytoskeleton, affecting chromatin diffusivity and organization. Decoding such pieces of these multiscale connections lays the groundwork for solving the genotype-to-phenotype puzzle in biology.

The substrate for the repair of DNA damage in living cells is not DNA but chromatin. Chromatin bears a range of modifications, which in turn bind ligands that compact or open chromatin structure, and determine its spatial organization within the nucleus. In some cases, RNA in the form of RNA:DNA hybrids or R-loops modulates DNA accessibility. Each of these parameters can favor particular pathways of repair. Chromatin or nucleosome remodelers are key regulators of chromatin structure, and a number of remodeling complexes are implicated in DNA repair. We cover novel insights into the impact of chromatin structure, nuclear organization, R-loop formation, nuclear actin, and nucleosome remodelers in DNA double-strand break repair, focusing on factors that alter repair functional upon ablation.

Mammalian chromosomes form a hierarchical structure within the cell nucleus, from chromatin loops, megabase (Mb)-sized topologically associating domains (TADs) to larger-scale A/B compartments. The molecular basis of the structures of loops and TADs has been actively studied. However, the A and B compartments, which correspond to early-replicating euchromatin and late-replicating heterochromatin, respectively, are still relatively unexplored. In this review, we focus on the A/B compartments, discuss their close relationship to DNA replication timing (RT), and introduce recent findings on the features of subcompartments revealed by detailed classification of the A/B compartments. In doing so, we speculate on the structure, potential function, and developmental dynamics of A/B compartments and subcompartments in mammalian cells.

Cell junctions integrate extracellular signals with intracellular responses to polarize tissues, pattern organs, and maintain tissue architecture by promoting cell–cell adhesion and communication. In this review, we explore the mechanisms whereby the adhesive junctions, adherens junctions and desmosomes, co-assemble and then segregate into unique plasma membrane domains. In addition, we highlight emerging evidence that these junctions are spatially and functionally integrated with the endoplasmic reticulum to mediate stress sensing and calcium homeostasis. We conclude with a discussion of the role of the endoplasmic reticulum in the mechanical stress response and how disruption of these connections may cause disease.

Challenging mechanochemical environments (i.e., with varied mechanical and adhesive properties) are now known to induce a wide range of adaptive phenomena in motile cells. For instance, confinement and low adhesion may trigger a phenotypic transition to fast amoeboid (leader bleb-based) migration. The molecular mechanisms that underly these phenomena are beginning to be understood. Due to its size, the mechanical properties of the nucleus have been shown to limit and facilitate cell migration. Additionally, the activity of various transient receptor potential (TRP) channels is now known to be integral to cell migration in response to a multitude of biophysical stimuli. How cells integrate signals from the nucleus and plasma membrane, however, is unclear. The development of therapeutics that suppress cancer or enhance immune cell migration for immuno-oncology applications, etc., will require additional work to completely understand the molecular mechanisms that enable cells to navigate mechanochemically challenging environments.

Lipid droplets (LDs) are subcellular organelles that play an integral role in lipid metabolism by regulating the storage and release of fatty acids, which are essential for energy production and various cellular processes. Lipolysis and lipophagy are the two major LD degradation pathways that mediate the utilization of lipids stored in these organelles. Recent studies have further uncovered alternative pathways, including direct lysosomal LD degradation and LD exocytosis. Here, we highlight recent findings that dissect the molecular basis of these diverse LD degradation pathways. Then, we discuss speculations on the crosstalk among these pathways and the potential unconventional roles of LD degradation.

Paraspeckle nuclear bodies form when the NEAT1 long noncoding RNA is transcribed and bound by multiple RNA-binding proteins. First described 20 years ago, in recent years a growing appreciation of paraspeckle dynamics has led to new understandings, in both structure and function. Structurally, paraspeckles form via distinct physico-chemical domains arising from the composition of key proteins, recruited to different parts of NEAT1. These domains interact, creating a core–shell structured paraspeckle via microphase separation. Functionally, many environmental, chemical, and mechanical triggers can alter paraspeckle abundance, with important consequences depending on the cell type, developmental stage, and trigger identity. Underpinning these insights are new tools for paraspeckle research, including screening assays, proximity-based identification tools, and RNA processing modulators. A picture is emerging of paraspeckles as gene regulatory condensates in many healthy and disease settings. Critically, however, paraspeckle functional importance is generally most apparent when cells and organisms face external stressors.

Cells have evolved mechanisms to migrate for diverse biological functions. A process frequently deployed during metazoan cell migration is the epithelial–mesenchymal transition (EMT). During EMT, adherent epithelial cells undergo coordinated cellular transitions to mesenchymalize and reduce their intercellular attachments. This is achieved via tightly regulated changes in gene expression, which modulates cell–cell and cell–matrix adhesion to allow movement. The acquisition of motility and invasive properties following EMT allows some mesenchymal cells to migrate through complex environments to form tissues during embryogenesis; however, these processes may also be leveraged by cancer cells, which often co-opt these endogenous programs to metastasize. Post-transcriptional regulation is now emerging as a major conserved mechanism by which cells modulate EMT and migration, which we discuss here in the context of vertebrate development and cancer.

Synthesizing the recent progresses, we present our perspectives on how local modulations of membrane curvature, tension, and bending energy define the feedback controls over membrane traffic processes. We speculate the potential mechanisms of, and the control logic behind, the different membrane mechanics-mediated feedback in endocytosis and exo-endocytosis coupling. We elaborate the path forward with the open questions for theoretical considerations and the grand challenges for experimental validations.