Review Articles

The metabolism of somatic stem cells must be regulated to meet their specific needs, to enable long-term maintenance as well as their activation, proliferation and subsequent differentiation. Better understanding of metabolic regulation in stem cells will open new opportunities to manipulate stem cell function, with potential applications in tissue regeneration and cancer prevention.

E3 ubiquitin ligases ensure the precise spatiotemporal control of key molecules during important cellular processes. This Review discusses the crucial roles of E3 ligases during early mammalian development and their roles in human disease, and considers how new methods to manipulate the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.

Mammalian RNA polymerase II transcribes protein-coding genes and non-coding transcription units, including long non-coding RNAs (lncRNAs). Studies applying recently developed nascent transcriptomics technology have revealed differences in transcription initiation and termination between lncRNAs and protein-coding genes, bearing relevance to genomic stress and DNA damage.

The majority of macromolecules are transported across the nuclear membrane by the Karyopherin-β (Kap) proteins, comprising importins, exportins and biportins. Unravelling mechanisms and regulation of Kap–cargo interactions is essential for understanding nuclear export and import of proteins and RNA and how this traffic impacts their physiological functions.

Lysine acetyltransferases and lysine deacetylases regulate gene expression and protein function by controlling acetylation and deacetylation of histones and diverse non-histone proteins. The activity of lysine acetyltransferases and lysine deacetylases is regulated by cellular metabolic states, offering the potential for therapeutic modulation through dietary and pharmacological interventions.

X chromosome inactivation in mammals involves chromosome-wide gene silencing at one X chromosome in cells of females, a process that requires complex spatiotemporal regulation. Recent findings provide new insights into the mechanisms and dynamics of X chromosome inactivation and the accompanying 3D reshaping of the chromosome.

Aneuploidy affects organisms from early development through to aging and is a cause of pregnancy loss and cancer. Recent studies have increased our understanding of its mechanisms and how it can be both beneficial and detrimental to cells and organisms, depending on the karyotype and external cues. These insights shed light on its roles in human pathogenesis and on genome evolution.

Mitochondrial permeability transition — mediated by the opening of the so-called mitochondrial permeability transition pore — causes abrupt flux of low molecular weight solutes across the generally impermeable inner mitochondrial membrane. Recent studies provide new insights into the molecular nature and mechanisms of the mitochondrial permeability transition pore and the physiological consequences of its opening.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses rely on a cohort of specialized viral proteins to transcribe and replicate their RNA genomes. Recent studies have improved our understanding of coronavirus RNA translation, replication and transcription, and offer new therapeutic targets.

Double-stranded RNAs (dsRNAs) are recognized by designated cellular sensors to mount an immune response. Although dsRNAs are generally of viral origin, dysregulation of several cellular processes can lead to accumulation of endogenous dsRNAs. These self-derived dsRNAs are often associated with immune disorders, but their immunogenicity can also be exploited for immunotherapy.

Cells in the embryo are subject to autonomous and external mechanical forces that help steer embryonic tissue patterning. Technical developments, such as in vitro models of early embryos, allow probing of the roles of mechanical forces in animal and human embryonic development.

Small RNAs (microRNAs, siRNAs, piRNAs and others) function as agents of intercellular communication, particularly in development, reproduction, immunity and inheritance. Chen and Rechavi discuss mechanisms and roles of plant and animal small RNAs in the exchange of information between cells, organisms and even species.

Satellite cells are skeletal muscle stem cells that are largely quiescent. They are activated upon muscle damage and differentiate into muscle cells or return to quiescence. These processes are controlled by cell-intrinsic mechanisms and by signals from the niche, and are deregulated in ageing, leading to impaired muscle regeneration.

Mitochondrial respiration relies on five enzymatic complexes that couple electron transport with proton pumping, leading to ATP synthesis. Recent studies have shed new light on the organization, assembly and mechanisms of the respiratory complexes, including the formation of their larger assemblies — respiratory supercomplexes — and their roles in physiology.

Entry of SARS-CoV-2 into host cells is mediated by the interaction between the viral spike protein and its receptor angiotensin-converting enzyme 2, followed by virus–cell membrane fusion. Worldwide research efforts have provided a detailed understanding of this process at the structural and cellular levels, enabling successful vaccine development for a rapid response to the COVID-19 pandemic.

Recent studies have revolutionized our understanding of the interplay between mRNA poly(A) tails and the processes of translation and mRNA decay in the cytoplasm. Poly(A) tails interact with dedicated RNA-binding proteins and deadenylases, which together determine the impact of poly(A) tails on gene expression.

Integral membrane proteins make up around one quarter of the human proteome and are highly diverse in topology, biophysical features, structure and function. Their biogenesis involves multiple pathways for membrane targeting, insertion into the lipid bilayer, folding and assembly with other subunits. Recent biochemical and structural analyses have provided new insights into these mechanisms.

DNA polymerase theta (Polθ)-mediated end joining is a recently characterized DNA repair pathway that functions in various cellular contexts to repair DNA double-strand breaks that are not repaired by other pathways. Polθ-mediated end joining both helps maintain the genome and causes genome instability, and is an emerging therapeutic target in cancer.

Dietary restriction in rodents and non-human primates affects key nutrient-sensing signalling pathways to increase healthspan and lifespan. This Review discusses these geroprotective mechanisms and recent insights suggesting that dietary restriction results in similar molecular and metabolic changes in humans, contributing to the prevention of ageing-associated diseases.

Machine learning is becoming a widely used tool for the analysis of biological data. However, for experimentalists, proper use of machine learning methods can be challenging. This Review provides an overview of machine learning techniques and provides guidance on their applications in biology.