Cell Discovery最新文献

Inter-chromosomal interactions play a crucial role in 3D genome organization, yet the organizational principles and functional significances remain elusive. In general, lncRNA loci and transcripts are frequently associated with transcriptional programs modulated by long-range chromatin interactions. Here, we identified a novel lncRNA named Gm26793, which is abundantly distributed in the primitive streak and mesodermal cells of embryonic day 7.5 mouse gastrula. Through genetic ablation of Gm26793, we observed a preferential responsiveness to primitive endoderm lineage during stem cell differentiation, as well as enhanced occurrence of transient and degenerative state cells in early mouse embryos when the cell fate segregates between epiblast and primitive endoderm. Mechanistically, we revealed that the genomic locus of Gm26793, rather than the lncRNA transcript or adjacent gene, governs the cell fate preference towards primitive endoderm. Concretely, Gm26793 locus (Chromosome 7) forms an inter-chromosomal molecular lock with Cubn (Chromosome 2) via CTCF, restraining the expression of Cubn and maintaining a natural epigenetic landscape, thus ensuring the proper lineage specification in vitro and in vivo. Overall, our study provides a clear paradigm that inter-chromosomal interaction collaborates with architectural factors to stabilize nuclear conformation and guarantee faithful gene expression during stem cell differentiation and mammalian embryogenesis.

Alternative polyadenylation (APA) is critical for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3' untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3' UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation "writer" catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic "eraser". Clinically, elevated levels of both LDHA and NUDT21, as well as increased K23-lactylated NUDT21, are associated with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.

The red/far-red light receptor phytochrome B (phyB) plays essential roles in regulating various plant development processes. PhyB exists in two distinct photoreversible forms: the inactive Pr form and the active Pfr form. phyB-Pfr binds phytochrome-interacting factors (PIFs) to transduce red light signals. Here, we determined the cryo-electron microscopy (cryo-EM) structures of the photoactivated phyB-Pfr‒PIF6 complex, the constitutively active mutant phyB^Y276H‒PIF6 complex, and the truncated phyBN^Y276H‒PIF6 complex. In these structures, two parallel phyB-Pfr molecules interact with one PIF6 molecule. Red light-triggered rotation of the PΦB D-ring leads to the conversion of hairpin loops into α helices and the "head-to-head" reassembly of phyB-Pfr N-terminal photosensory modules. The interaction between phyB-Pfr and PIF6 influences the dimerization and transcriptional activation activity of PIF6, and PIF6 stabilizes the N-terminal extension of phyB-Pfr and increases the Pr→Pfr photoconversion efficiency of phyB. Our findings reveal the molecular mechanisms underlying Pr→Pfr photoconversion and PIF6-mediated red light signal transduction of phyB.

Despite high vaccination rates, highly evolved Omicron variants have caused widespread infections and, in some cases, recurrent infections in the human population. As the population continues to be threatened by new variants, it is critical to understand how the dynamic cross-reactive antibody response evolves and affects protection. Here, we longitudinally profiled neutralizing antibodies in individuals who experienced three Omicron waves in China over an 18-month period following the lifting of the COVID restriction. We found that individuals with BA.5/BF.7 and XBB dual infections had increased breadth and neutralizing potency of Omicron-specific antibodies compared to those with a BA.5/BF.7 single infection, and were thus more resistant to JN.1/XDV.1 infection in the third wave. During the second infection, a new imprint based on the previously infected variant was established, and the antibodies developed high cross-reactivity against the Omicron variants and less against vaccine-derived WT SARS-CoV-2. Our results suggest that the high titer and breadth of cross-reactive antibodies from multiple infections may be protective against future infection with Omicron variants such as JN.1, but may still be vulnerable to antigenically advanced subvariants such as KP.3.1.1 and XEC.

Elucidating the regulatory mechanisms underlying the development of different brain regions in humans is essential for understanding advanced cognition and neuropsychiatric disorders. However, the spatiotemporal organization of three-dimensional (3D) chromatin structure and its regulatory functions across different brain regions remain poorly understood. Here, we generated an atlas of high-resolution 3D chromatin structure across six developing human brain regions, including the prefrontal cortex (PFC), primary visual cortex (V1), cerebellum (CB), subcortical corpus striatum (CS), thalamus (TL), and hippocampus (HP), spanning gestational weeks 11-26. We found that the spatial and temporal dynamics of 3D chromatin organization play a key role in regulating brain region development. We also identified H3K27ac-marked super-enhancers as key contributors to shaping brain region-specific 3D chromatin structures and gene expression patterns. Finally, we uncovered hundreds of neuropsychiatric GWAS SNP-linked genes, shedding light on critical molecules in various neuropsychiatric disorders. In summary, our findings provide important insights into the 3D chromatin regulatory mechanisms governing brain region-specific development and can serve as a valuable resource for advancing our understanding of neuropsychiatric disorders.

Purinergic P2Y2 receptor (P2Y2R) represents a typically extracellular ATP and UTP sensor for mediating purinergic signaling. Despite its importance as a pharmacological target, the molecular mechanisms underlying ligand recognition and G-protein coupling have remained elusive due to lack of structural information. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the apo P2Y2R in complex with G_q, ATP-bound P2Y2R in complex with G_q or G_o, and UTP-bound P2Y4R in complex with G_q. These structures reveal the similarities and distinctions of ligand recognition within the P2Y receptor family. Furthermore, a comprehensive analysis of G-protein coupling reveals that P2Y2R exhibits promiscuity in coupling with both G_q and G_o proteins. Combining molecular dynamics simulations and signaling assays, we elucidate the molecular mechanisms by which P2Y2R differentiates pathway-specific G_q or G_o coupling through distinct structural components on the intracellular side. Strikingly, we identify a helix-like segment within the N-terminus that occupies the orthosteric ligand-binding pocket of P2Y2R, accounting for its self-activation. Taken together, these findings provide a molecular framework for understanding the activation mechanism of P2Y2R, encompassing ligand recognition, G-protein coupling, and a novel N-terminus-mediated self-activation mechanism.

Psychological stress has profound impacts on the gastrointestinal tract via the brain‒gut axis. However, its effects on intestinal stem cells (ISCs) and the resulting implication for intestinal homeostasis remain poorly understood. Here, we observed a notable reduction in both the quantity and proliferative capacity of ISCs under chronic stress conditions, driven by elevated levels of corticosterone resulting from activation of the hypothalamic‒pituitary‒adrenal (HPA) axis. Mechanistically, corticosterone directly interacts with its receptor, nuclear receptor subfamily 3 group c member 1 (NR3C1), leading to increased expression of FKBP prolyl isomerase 5 (FKBP5) in ISCs. Subsequently, FKBP5 negatively regulates AKT activation by facilitating its dephosphorylation at Ser473, ultimately enhancing nuclear translocation of forkhead box O (FoxO) and inhibiting ISC proliferative activity. Consequently, ISC dysfunction contributes to the stress-driven exacerbation of DSS-induced colitis. Collectively, these findings reveal an intrinsic brain-to-gut regulatory pathway whereby psychological stress impairs ISC activity via corticosterone elevation, providing a mechanistic explanation for stress-enhanced susceptibility to colitis.

High altitude presents a challenging environment for human settlement. DNA methylation is an essential epigenetic mechanism that responds to environmental stimuli, but its roles in high-altitude short-term acclimatization (STA) and long-term adaptation (LTA) are poorly understood. Here, we conducted a methylome-wide association study involving 687 native highlanders and 299 acclimatized newcomers in the Tibetan Plateau and 462 native lowlanders to identify differentially methylated sites (DMSs) associated with STA or LTA. We identified 93 and 4070 DMSs for STA and LTA, respectively, which had no overlap, showed opposite asymmetric effect size patterns, and resided near genes enriched in distinct biological pathways/processes (e.g., cell cycle for STA and immune diseases and calcium signalling pathway for LTA). Epigenetic clock analysis revealed evidence of accelerated ageing in the acclimatized newcomers compared to the native lowlanders. Our research provides novel insights into epigenetic regulation in relation to high altitude and intervention strategies for altitude-related ageing or illnesses.