Pride holds a special place in the hearts of lesbian, gay, bisexual, transgender, queer, intersex, asexual+ (LGBTQIA+) individuals as a time to celebrate the progress we have made, and advocate for the advances yet to come. Here, I highlight ways in which the scientific community has had a crucial role in driving this progress, and provide a personal perspective on the importance of being open and

Carbon dioxide not only plays a central role in the carbon cycle, but also acts as a crucial signal in living cells. Adaptation to changing CO2 concentrations is critical for all organisms. Conversion of CO2 to HCO3− by carbonic anhydrase and subsequent HCO3−-triggered signalling are thought to be important for cellular responses to CO2 (refs. 1,2,3). However, carbonic anhydrases are suggested to transduce

Multiple methods for deriving human cortical organoids have been established in the past decade. A study now systematically compares patterning strategies and shows that combined WNT and dual SMAD inhibition is superior to dual SMAD inhibition alone in inducing robust cortical identity in 3D human pluripotent stem-cell aggregates.

Human naive pluripotent stem cells are generally believed to possess an unrestricted capacity to differentiate into both embryonic and extraembryonic lineages. However, two new studies now uncover a role for the Polycomb repressive complex 2 (PRC2) as a lineage gatekeeper that shields the potency of these cells.

In mammals, translational control plays critical roles during oocyte-to-embryo transition (OET) when transcription ceases. However, the underlying regulatory mechanisms remain challenging to study. Here, using low-input Ribo-seq (Ribo-lite), we investigated translational landscapes during OET using 30–150 mouse oocytes or embryos per stage. Ribo-lite can also accommodate single oocytes. Combining PAIso-seq

RNA processing plays a central role in accurately transmitting genetic information into functional RNA and protein regulators. To fully appreciate the RNA life-cycle, tools to observe RNA with high spatial and temporal resolution are critical. Here we review recent advances in RNA imaging and highlight how they will propel the field of RNA biology. We discuss current trends in RNA imaging and their

Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early Dual SMAD and WNT inhibition course is necessary and sufficient to establish robust and lasting cortical organoid NSC identity, efficiently

Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here we define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Our integrated analysis reveals

The lysosome is an essential organelle that degrades extra- and intra-cellular components and acts as a signaling hub. A study in Caenorhabditis elegans now shows that the lysosome mediates inter-tissue communication from periphery to neurons to regulate lifespan via fatty acid breakdown and secretion.

The nuclear pore complex (NPC) regulates transport of macromolecules into and out of the nucleus. A study now shows that mechanical force applied on the nucleus affects the transport rates across the NPC diffusion barrier, modulating the nuclear localization of certain cargos.

High-resolution maps of embryonic development suggest that acquisition of cell identity is not limited to canonical germ layers but proceeds via alternative routes. Despite evidence that visceral organs are formed via embryonic and extra-embryonic trajectories, the production of organ-specific cell types in vitro focuses on the embryonic one. Here we resolve these differentiation routes using massively

Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in ageing-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate ageing remains unclear. Here we report a fat-to-neuron lipid signalling pathway induced by lysosomal

Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic

Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem

Fibroblasts become activated during wound repair and rapidly return to a ‘resting’ state, and are thus critical for normal tissue homeostasis and tumour development. A new study now reveals an important pro-tumorigenic role for the stress response in cancer-associated fibroblasts that may offer a new opportunity to limit tumour progression.

The distinct activities of organelles depend on the proper function of their membranes. Coordinated membrane biogenesis of different organelles necessitates lipid transport from their site of synthesis to their destination. Several factors have been proposed to participate in lipid distribution, but despite its basic importance, in vivo evidence linking the absence of putative transport pathways to

Various mechanisms contribute to membrane repair1,2,3,4,5,6,7,8 but the machinery that mediates the repair of large wounds on the plasma membrane is less clear. We found that shortly after membrane damage, Tetraspanin-enriched macrodomains are assembled around the damage site. Tetraspanin-enriched macrodomains are in the liquid-ordered phase and form a rigid ring around the damaged site. This restricts

Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced

Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in β-cells to suppress glycolysis and ATP-dependent

The first lineage choice in human embryo development separates trophectoderm from the inner cell mass. Naïve human embryonic stem cells are derived from the inner cell mass and offer possibilities to explore how lineage integrity is maintained. Here, we discover that polycomb repressive complex 2 (PRC2) maintains naïve pluripotency and restricts differentiation to trophectoderm and mesoderm lineages

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3′ UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3′ UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the

N6-methyladenosine (m6A) and its regulatory components play critical roles in various developmental processes in mammals. However, the landscape and function of m6A in early embryos remain unclear owing to limited materials. Here we developed a method of ultralow-input m6A RNA immunoprecipitation followed by sequencing to reveal the transcriptome-wide m6A landscape in mouse oocytes and early embryos

Intracellular organelles change their size during trafficking and maturation. This requires the transport of ions and water across their membranes. Macropinocytosis, a ubiquitous form of endocytosis of particular importance for immune and cancer cells, generates large vacuoles that can be followed optically. Shrinkage of macrophage macropinosomes depends on TPC-mediated Na+ efflux and Cl− exit through

Low expression levels and stoichiometric imbalances of long noncoding RNAs (lncRNAs) are often used as evidence for their probable lack of function or for limiting the scope of their potential influence. Recent advances in our understanding of the substoichiometric functions of lncRNAs challenge these notions and suggest routes through which unabundant lncRNAs can affect cellular functions and gene

Although cardiac cell therapy has been intensely studied, the high expectations are still an unmet goal. A study now characterizes the translational potential and mode of action of human ventricular progenitors (HVPs) derived from embryonic stem cells, as a source for cardiac cell therapy.

The contribution of the epicardium, the outermost layer of the heart, to cardiac regeneration has remained controversial due to a lack of suitable analytical tools. By combining genetic marker-independent lineage-tracing strategies with transcriptional profiling and loss-of-function methods, we report here that the epicardium of the highly regenerative salamander species Pleurodeles waltl has an intrinsic

WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. Here we provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels

The vasculature is an essential organ for the delivery of blood and oxygen to all tissues of the body and is thus relevant to the treatment of ischaemic diseases, injury-induced regeneration and solid tumour growth. Previously, we demonstrated that ETV2 is an essential transcription factor for the development of cardiac, endothelial and haematopoietic lineages. Here we report that ETV2 functions as

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes

Centromeres are defined epigenetically by the histone H3 variant CENP-A. The propagation cycle by which pre-existing CENP-A nucleosomes serve as templates for nascent assembly predicts the epigenetic memory of weakened centromeres. Using a mouse model with reduced levels of CENP-A nucleosomes, we find that an embryonic plastic phase precedes epigenetic memory through development. During this phase

Acute trauma stimulates local repair mechanisms but can also impact structures distant from the injury, for example through the activity of circulating factors. To study the responses of remote tissues during tissue regeneration, we profiled transcriptomes of zebrafish brains after experimental cardiac damage. We found that the transcription factor gene cebpd was upregulated remotely in brain ependymal

How are haematopoietic stem cells (HSCs) protected from inflammation, which increases with age and can deplete HSCs? Adiponectin, an anti-inflammatory factor that is not required for HSC function or haematopoiesis, promotes stem/progenitor cell proliferation after bacterial infection and myeloablation. Adiponectin binds two receptors, AdipoR1 and AdipoR2, which have ceramidase activity that increases

Dynamic morphological changes of intracellular organelles are often regulated by protein phosphorylation or dephosphorylation1,2,3,4,5,6. Phosphorylation modulates stereospecific interactions among structured proteins, but how it controls molecular interactions among unstructured proteins and regulates their macroscopic behaviours remains unknown. Here we determined the cell cycle-specific behaviour

Cytosolic DNA sensing by the cGAS–STING pathway is critical for sustaining an innate immune defense program. A new study shows that the cGAS–STING pathway signals by a non-canonical mechanism to control protein translation through the unfolded protein response sensor PERK, and thereby contributes to cellular senescence and organ fibrosis.

Innate DNA sensing via the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) mechanism surveys microbial invasion and cellular damage and thus participates in various human infectious diseases, autoimmune diseases and cancers. However, how DNA sensing rapidly and adaptively shapes cellular physiology is incompletely known. Here we identify the STING–PKR-like endoplasmic reticulum

Phosphoinositide signalling regulates cellular processes and is hijacked by pathogens. Classically, phosphoinositides are produced by kinase- and phosphatase-catalysed reactions. A study now reveals an unprecedented, kinase- and ATP-free synthesis of PtdIns(3,4)P2 via a phosphotransferase mechanism during bacterial infection.

Despite their low abundance, phosphoinositides play a central role in membrane traffic and signalling. PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are uniquely important, as they promote cell growth, survival and migration. Pathogenic organisms have developed means to subvert phosphoinositide metabolism to promote successful infection and their survival in host organisms. We demonstrate that PtdIns(3,4)P2 is

Parental DNA methylation and histone modifications undergo distinct global reprogramming in mammalian pre-implantation embryos, but the landscape of epigenetic crosstalk and its effects on embryogenesis are largely unknown. Here we comprehensively analyse the association between DNA methylation and H3K9me3 reprogramming in mouse pre-implantation embryos and reveal that CpG-rich genomic loci with high

The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from haemogenic endothelium (HE) in a NOTCH- and retinoic acid (RA)-dependent manner. Although a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA+ definitive

Human NANOG expression resets stem cells to ground-state pluripotency. Here we identify the unique features of human NANOG that relate to its dose-sensitive function as a master transcription factor. NANOG is largely disordered, with a C-terminal prion-like domain that phase-transitions to gel-like condensates. Full-length NANOG readily forms higher-order oligomers at low nanomolar concentrations,

A decline in skeletal muscle mass and low muscular strength are prognostic factors in advanced human cancers. Here we found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in muscle through extracellular-vesicle-encapsulated miR-122, which targets O-GlcNAc transferase (OGT). Mechanistically, O-GlcNAcylation of ryanodine receptor 1 (RYR1) competed with NEK10-mediated

The disassembly of integrin-containing focal adhesions (FAs) at mitotic entry is essential for cell rounding, mitotic retraction fibre formation, bipolar spindle positioning and chromosome segregation. The mechanism that drives FA disassembly at mitotic entry is unknown. Here, we show that the CDK1–cyclin B1 complex phosphorylates the integrin activator kindlin, which results in the recruitment of

Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase is thought to be the primase for mtDNA replication. However, it is unclear how this enzyme, which normally transcribes long polycistronic RNAs, can produce short RNA oligonucleotides to initiate mtDNA replication. We show that the PPR domain of Drosophila mitochondrial

Organic acidurias are inherited disorders that can severely affect mitochondria. A study in Caenorhabditis elegans suggests that binding of a toxic metabolite to a factor crucial for mitochondrial structure may contribute to disease mechanisms.

d-2-Hydroxyglutarate (D-2HG) is an α-ketoglutarate-derived mitochondrial metabolite that causes d-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up

Intercellular communication orchestrates a multitude of physiologic and pathologic conditions. Algorithms to infer cell–cell communication and predict downstream signalling and regulatory networks are needed to illuminate mechanisms of stem cell differentiation and tissue development. Here, to fill this gap, we developed and applied CellComm to investigate how the aorta–gonad–mesonephros microenvironment

Pluripotent stem cells can be driven by manipulation of Wnt signalling through a series of states similar to those that occur during early embryonic development, transitioning from an epithelial phenotype into the cardiogenic-mesoderm lineage and ultimately into functional cardiomyocytes. Strikingly, we observed that initiation of differentiation in induced pluripotent stem cells (iPSCs) and embryonic

Multiplexed modulation of endogenous genes is crucial for sophisticated gene therapy and cell engineering. CRISPR–Cas12a systems enable versatile multiple-genomic-loci targeting by processing numerous CRISPR RNAs (crRNAs) from a single transcript; however, their low efficiency has hindered in vivo applications. Through structure-guided protein engineering, we developed a hyper-efficient Lachnospiraceae

The world of small noncoding RNAs (sncRNAs) is ever-expanding, from small interfering RNA, microRNA and Piwi-interacting RNA to the recently emerging non-canonical sncRNAs derived from longer structured RNAs (for example, transfer, ribosomal, Y, small nucleolar, small nuclear and vault RNAs), showing distinct biogenesis and functional principles. Here we discuss recent tools for sncRNA identification

Overload of proteasomal clearance triggers formation of a large protein inclusion called the aggresome, which shares similarities with protein aggregates seen in neurodegenerative diseases such as Huntington’s. A new study uncovers how centrosome and centriolar satellite components facilitate stepwise assembly of aggresomes.

Biomolecular condensation has emerged as a fundamental mechanism for cellular organization, but less is known about the regulation of condensate subcellular location and size. A new study reports that membrane tethering of protein and RNA directly influences the assembly, size and material properties of ribonucleic condensates.

Skeletal muscle has long been recognized as an inhospitable site for disseminated tumour cells (DTCs). Yet its antimetastatic nature has eluded a thorough mechanistic examination. Here, we show that DTCs traffic to and persist within skeletal muscle in mice and in humans, which raises the question of how this tissue suppresses colonization. Results from mouse and organotypic culture models along with

Epithelial–mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E–M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance

Biomolecular condensates organize biochemistry, yet little is known about how cells control the position and scale of these structures. In cells, condensates often appear as relatively small assemblies that do not coarsen into a single droplet despite their propensity to fuse. Here, we report that ribonucleoprotein condensates of the glutamine-rich protein Whi3 interact with the endoplasmic reticulum