Reviews & Analysis

Stem cells are well known to be controlled transcriptionally, but recent studies indicate that pluripotency, cell fate and differentiation depend on the regulation of translation and ribosome biogenesis by mTOR signalling, ribosome levels, and mRNA and tRNA features. Elucidating these stem cell regulatory mechanisms may increase our understanding of tumorigenesis.

Myopathies are genetically inherited diseases that affect the structure and/or function of skeletal muscles and often result in muscle degeneration (muscular dystrophy). This Review discusses our current understanding of the cellular and molecular mechanisms that underlie the most common of these pathologies, which provide key insights into muscle biology.

The orientation of cell divisions regulates tissue architecture and cell fate and depends on mitotic spindle positioning, which is controlled by intracellular and extracellular cues. Building on work in invertebrate systems, recent studies addressed how these mechanisms operate in vertebrates, and provided initial insights into their roles in vertebrate tissue development and homeostasis.

Expansion of short tandem repeats can impair RNA and protein function and cause diseases through four main mechanisms: transcription repression, RNA gelation and sequestration of RNA-binding proteins, protein gain of function, and repeat-associated non-AUG toxic translation. Synergy between these mechanisms exacerbates disease, but also offers promising therapeutic targets.

Bacteriophage anti-CRISPR proteins evolved to counter CRISPR–Cas-mediated immunity in prokaryotes. Recent structural studies have provided novel insights into the mechanisms and functions of anti-CRISPRs, and have increased the breadth of their use for biotechnology applications in eukaryotes.

Liver regeneration involves multiple cell types, including hepatocytes, hepatic stellate cells, endothelial cells and inflammatory cells. Recent studies have elucidated the interactions between these cells during regeneration as well as the mechanisms that regulate cell proliferation and fibrosis remodelling, and have uncovered macrophages as key players. Such findings can help design novel therapeutic approaches.

The canonical function of endocytosis is molecule internalization. Beyond this role, endocytic trafficking has emerged as a process central to the spatiotemporal regulation of cell signalling. Endocytic trafficking thus controls many cellular processes and tissue-wide properties, including cell migration and polarity, and its deregulation has been implicated in pathologies, particularly cancer.

Cells can sense various signals, including chemical, mechanical, geometric and electrical signals, and migrate towards or away from them. Such directed cell migration involves signal generation, sensing and transduction that eventually lead to polarized force generation. Deciphering the mechanisms underlying these processes is crucial to understanding cell migration in vivo.

Recent technological breakthroughs in mapping and visualizing chromatin contacts have considerably improved our understanding of 3D genome organization and function. This Review discusses the features, strengths and limitations of various methods of genome organization analysis, including sequencing-based techniques, microscopy-based techniques and computational and modelling approaches.

The cytoskeleton has been extensively implicated in regulating cell function and behaviour during development. This Review analyses the functional organization of cytoskeletal components in the early mouse embryo, and discusses key roles of the cytoskeleton during early mammalian embryogenesis, including regulation of cell fate specification and morphogenesis of the blastocyst.

High-resolution imaging technologies have revealed that all living organisms localize mRNAs in subcellular compartments, creating translation hotspots that locally tune gene expression. Insight has been gained into the mechanisms of mRNA transport and local mRNA translation, including into the role of messenger ribonucleoproteins and higher-order RNA granules in these processes.

Stromal progenitor cells contribute to the maintenance of tissue homeostasis in different organs. In vitro, these mesenchymal stromal cells (MSCs) can differentiate into many cell types. Recent omics and single-cell studies provide insights into the gene regulatory networks that drive lineage determination and cell differentiation, which has implications for the understanding of human diseases and for the development of cell-based therapies.

MicroRNAs widely regulate systemic metabolism, prominently that of glucose and lipids. Consequently, microRNA misexpression can lead to metabolic diseases such as diabetes and atherosclerosis. MicroRNAs are therefore emerging as potential therapeutic targets to control metabolism and, owing to their secretion in extracellular vesicles, as metabolic biomarkers.

Chromatin loops are proposed to be formed through loop extrusion by structural maintenance of chromosomes (SMC) complexes. Recent studies have shown that the SMC complexes condensin and cohesin are indeed able to extrude DNA, and caused a paradigm shift in our understanding of genome organization and the cellular functions of SMC complexes.

Brown and beige adipocytes are mammalian thermogenic fat cells that regulate whole-body energy metabolism. Notably, brown/beige adipocytes are heterogeneous and their functions extend beyond thermogenesis, encompassing roles as metabolite sinks, as secretory cells and as regulators of adipose tissue homeostasis. Thus, induction of brown/beige fat activity correlates with improved metabolic health.

The histone modifiers Polycomb repressive complex 1 (PRC1) and PRC2 have important roles in development and disease, especially cancer. Recent studies have revealed the existence of various mutually exclusive PRC1 and PRC2 variants, and provided new insights into their molecular functions and physiological importance.

Transfer RNAs (tRNAs) are heavily modified post-transcriptionally, and the number and types of modifications are continually expanding. Recent studies show that tRNA modifications can be altered in response to cellular and environmental stresses, and that deficiencies in tRNA modification can cause mitochondrial diseases, neurological disorders and cancer.

Direct reprogramming converts cells from one lineage into cells of another without going through an intermediary pluripotent state. This Review describes our current understanding of the molecular mechanisms underlying direct reprogramming as well as the progress in improving its efficiency and the maturation of reprogrammed cells, and the challenges associated with its translational applications.

The majority of mitochondrial proteins are encoded in the nucleus, but mitochondria have an independent protein synthesis machinery that is required for the biogenesis of the respiratory chain. Recent insights into the mechanisms and regulation of mitochondrial protein synthesis have increased our understanding of mitochondrial function and its integration with cell physiology.

Recently determined structures of the telomere maintenance protein complexes shelterin and CST shed new light on the regulation of telomere DNA replication and chromosome end-capping, and on how disease-causing mutations in their encoding genes may affect their functions.