Cell reports最新文献

Human pluripotent stem cells (hPSCs) can self-renew indefinitely and differentiate into all three embryonic germ layers. We previously defined the essentialome of hPSCs using a genome-wide CRISPR screen, but the functions of each gene remain obscure. Here, we used a pooled single-cell CRISPR screen to investigate pluripotent-specific essential transcription factors (TFs). We found that most TFs form a highly interconnected gene regulatory network (GRN) that governs key aspects of pluripotency, including self-renewal, differentiation, survival, and transposable element expression. Interestingly, we identify multiple TFs that act as lineage-specific gatekeepers, blocking exit from pluripotency, and others that inhibit pluripotency, potentially balancing self-renewal and differentiation responsiveness. Finally, perturbing the GRN in naive hPSCs revealed both conserved and state-specific regulatory roles relative to primed cells. Altogether, our analysis defines an extended GRN for human pluripotency, offering insights into early human development. These findings may inform strategies to improve hPSC-based disease models and regenerative therapies.

Objects move through space and time, generating sequential visuotopic activations in all sighted animals, leading to velocity perception defined by direction and speed. The primary visual cortex (V1) only encodes directionality at low speed, yet we effortlessly perceive velocities ranging from 0.25°/s to 500°/s. To resolve this paradox, we recorded neuronal responses to moving dots, gratings, and movies across the lateral geniculate nucleus (LGN), V1, middle temporal (MT) area, and medial superior temporal (MST) area of the macaque motion pathway. Regardless of cell type and motion stimuli, V1 neurons lost direction selectivity at ∼29°/s, while MT and MST neurons maintained it up to ∼82°/s and ∼183°/s, respectively. A cascaded spatiotemporal integration model reveals that at each cortex, direction-selective neurons can generate velocity selectivity de novo by integrating sequential visuotopic activations from preceding areas, irrespective of speed and directionality. Computing velocity anew by shifting "gears" within the motion hierarchy offers insights for information processing in other species, modalities, and machine vision.

Post-traumatic stress disorder (PTSD) develops following exposure to a traumatic event. However, effective prevention and treatments remain elusive. In this study, we report that sub-anesthetic doses of dexmedetomidine can alleviate fear in mice by inhibiting the consolidation of fear memory. Transcriptomic analysis identifies sterol regulatory element-binding protein 1 (Srebf1) as a key mediator of dexmedetomidine's effects. The potential mechanism of this involves dexmedetomidine reducing the nuclear translocation of Srebf1 specifically in prelimbic prefrontal cortex astrocytes, thereby decreasing the active transcriptional form of Srebf1. This results in the downregulation of its target gene, phosphoglycerate dehydrogenase (Phgdh). Phgdh, as the main synthetase of the N-methyl-D-aspartate receptor co-agonist D-serine, plays a crucial role in regulating synaptic stability and ultimately inhibiting the consolidation of fear memory. This work identifies the mechanism by which dexmedetomidine inhibits fear memory consolidation, providing a rationale for its preventive application and uncovering novel targets for PTSD intervention.

T helper 17 (Th17) cells are pivotal in mucosal defense and autoimmune pathology, with their function governed by the transcription factor retinoic acid receptor-related orphan receptor gamma t (RORγt). Although genome-wide association studies link RORC variants to inflammatory diseases, their functional consequences remain poorly understood. We identify a pathogenic RORγt mutation N277D (mouse homolog N275D) that amplifies Th17 pathogenicity through cooperation with hypoxia-inducible factor HIF-1α. This mutation enhances IFN-γ and other Th1-type cytokine production by Th17 cells, exacerbating colitis without disrupting T cell development or homeostasis. Integrated transcriptomic and metabolomic profiling reveals activation of glycolytic and hypoxia-associated pathways, consistent with increased RORγt^N275D recruitment by HIF-1α to the Pdk1 locus. Notably, silencing Pdk1 normalizes the excessive IFN-γ production in RORγt^N275D Th17 cells. Together, these findings define a regulatory axis linking RORγt and HIF-1α that coordinates transcriptional and metabolic programs in pathogenic Th17 cells, providing a framework for dissecting the functional impact of autoimmune risk variants.

Children with favorable-histology Wilms tumor (FHWT) who relapse or whose tumors show blastemal predominance post-chemotherapy often face poor outcomes. The purpose of this study is to identify mechanisms of chemotherapy resistance in FHWT. We induce a patient-derived xenograft model (KT-47) to develop blastemal predominance after chemotherapy and to become resistant to vincristine, actinomycin-D, and doxorubicin (VAD). Multi-omics analyses reveal chromatin and transcriptional changes, including increased H3K4me3 and decreased H3K27me3 at stem cell and nephrogenesis gene loci. LIN28B is the most upregulated resistance-associated gene, linked to MYCN copy gain/upregulation and chromatin remodeling. ABCB1 expression correlates with interchromosomal enhancer interactions and functions as the mediator of chemotherapy resistance in vitro. These findings are validated in additional Wilms tumor models. Overall, resistance is associated with de-differentiation to a stem-like state and is driven by ABCB1 upregulation, suggesting that therapeutic strategies targeting chromatin regulation and drug efflux may be relevant in therapy-resistant Wilms tumor.

Adenosine-to-inosine RNA editing by ADAR1 prevents aberrant innate immunity activation by modifying endogenous double-stranded RNA. Mice carrying a left-handed double-stranded RNA (Z-RNA) binding-deficient mutation develop Aicardi-Goutières syndrome (AGS)-like encephalopathy, characterized by ventricular enlargement, gliosis, calcification, and white matter degeneration with a type I interferon (IFN) signature. However, the mechanisms underlying encephalopathy development remain unknown. Here, we show that pathology was most severe in periventricular regions where IFN-stimulated gene (ISG) expression was elevated and ependymal cells were lost, accompanied by higher IFN-α levels in cerebrospinal fluid than in sera. Blocking type I IFN signaling fully reversed these abnormalities, which was not achieved by deleting downstream PKR or ZBP1. Microglial elimination partially alleviated the encephalopathy without suppressing ISGs. In contrast, neuron- or astrocyte-specific ADAR1 dysfunction evoked robust ISG expression and recapitulated AGS-like encephalopathy, with astrocytic dysfunction causing particularly severe effects. These findings identify aberrant multicellular IFN signaling as the central driver of AGS-like encephalopathy.

Accurate numerical cognition relies on representing and comparing quantities, a fundamental skill for adaptive behavior. In nonhuman primates, the parieto-frontal network, including the ventral intraparietal area (VIP) and prefrontal cortex (PFC), supports this process, but the functional dynamics and directionality of communication between these regions remain unclear. We examine population-level interactions of simultaneously recorded neuronal activity between VIP and PFC in two male macaques performing a numerosity task. Using time-lagged canonical correlation analyses, we show that correct trials exhibit sustained correlations driven by numerosity-selective neurons, with early feedforward dominance from VIP to PFC following sample onset. By contrast, error trials show weaker correlations, reduced VIP-to-PFC feedforward signaling, and transient breakdowns during the late working memory period. These findings show that coordinated parieto-frontal population activity enables accurate numerical judgments, whereas disrupted interactions impair performance, highlighting the critical role of dynamic, task-dependent interareal communication in categorical decisions.

Different classes of anesthetics induce unconsciousness despite acting through distinct molecular mechanisms, raising the possibility that their convergent effects arise at the level of the dynamics of neural population activity. To explore this, we analyze intracortical electrophysiological recordings during infusions of propofol, ketamine, and dexmedetomidine, applying a rigorous method to estimate the stability of population dynamics during anesthesia. We find that all three anesthetics, despite their molecular differences, similarly affect cortical states by reducing dynamic stability. The estimated destabilization is corroborated by the slower recovery from sensory perturbations and longer stimulus-induced autocorrelation times observed during the anesthetic infusions. Destabilization is most prevalent in the low-frequency band of the population dynamics, linking it to the well-known increase in low-frequency power during anesthesia. Together, these findings suggest that cortical destabilization may be a shared neural correlate of anesthetic-induced unconsciousness and provide a plausible link to the low-frequency oscillations observed during anesthesia.

The human skin microbiome is essential for health and is shaped by both host and environmental factors. To establish a nationwide baseline, we profile the skin microbiome of 1,029 Chinese individuals across three body sites (hand, axilla, and foot), four geographic regions, and four ethnic groups using 16S rRNA gene sequencing. Within each skin site, we identify two cutotypes, one of which is consistently dominated by Staphylococcus. Microbial diversity and community composition vary across body sites, geography, ethnicity, gender, and age, with geographic location emerging as the strongest source of variation and enabling accurate classification by Random Forest models. Notably, Han and minority populations within the same region exhibit greater similarity than the same ethnic group across different regions. Aging-related shifts differ by both body site and geography, reflecting interactions between physiological and environmental influences. This population-scale study provides a comprehensive reference for the Chinese skin microbiome and reveals how host and environmental factors jointly structure skin microbial communities.

Metabolic regulation is central to the tumor suppressor function of p53. By analyzing the human patients with autoimmune diseases, we found that p53 expression was significantly reduced in Treg cells, negatively correlating with abnormally elevated BCL-6 levels. p53 loss causes dysregulated immune homeostasis and dampens Treg function in vitro and in vivo. Mechanistically, p53 transcriptionally activates ALDH6A1 expression and propionyl-CoA anabolism to upregulate functional Treg gene expression via histone propionylation. Treg-specific knockout of ALDH6A1 phenocopies the autoimmune responses of p53 deficiency, and propionyl-CoA restoration largely recovers Treg cell function in mice lacking p53 or ALDH6A1. Clinically, impaired p53-ALDH6A1-histone propionylation signaling is observed in patients with autoimmune diseases and correlates with poor efficacy of first-line therapies. Together, these findings reveal a direct connection between propionyl-CoA metabolism and histone modifications, which is governed by p53 and is crucial for Treg cell function and immune tolerance suppression.