Nature Communications最新文献

The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus.

Progeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report a whole genome, multiparametric CRISPR screen, identifying 43 genes that can rescue multiple cellular phenotypes associated with progeria. We implement the screen in fibroblasts from Néstor-Guillermo Progeria Syndrome male patients, carrying a homozygous A12T mutation in BAF. The hits are enriched for genes involved in protein synthesis, protein and RNA transport and osteoclast formation and are validated in a whole-organism Caenorhabditis elegans model. We further confirm that BAF A12T can disrupt protein synthesis rate and fidelity, which could contribute to premature aging in patients. This work highlights the power of multiparametric genome-wide suppressor screens to identify genes enhancing cellular resilience in premature aging and provide insights into the biology underlying progeria-associated cellular dysfunction.

Mechanotransduction channels are widely expressed in both vertebrates and invertebrates, mediating various physiological processes such as touch, hearing and blood-pressure sensing. While previously known mechanotransduction channels in metazoans are primarily cation-selective, we identified Anoctamin-1 (ANOH-1), the C. elegans homolog of mammalian calcium-activated chloride channel ANO1/TMEM16A, as an essential component of a mechanosensory channel complex that contributes to the nose touch mechanosensation in C. elegans. Ectopic expression of either C. elegans or human Anoctamin-1 confers mechanosensitivity to touch-insensitive neurons, suggesting a cell-autonomous role of ANOH-1/ANO1 in mechanotransduction. Additionally, we demonstrated that the mechanosensory function of ANOH-1/ANO1 relies on CIB (calcium- and integrin- binding) proteins. Thus, our results reveal an evolutionarily conserved chloride channel involved in mechanosensory transduction in metazoans, highlighting the importance of anion channels in mechanosensory processes.

Clustered protocadherins (cPcdhs) belong to the cadherin superfamily and play important roles in neural development. cPcdhs mediate homophilic adhesion and lead to self-avoidance and tiling by giving neurons specific identities in vertebrates. Structures and functions of cPcdhs have been studied extensively in past decades, but the mechanisms behind have not been fully understood. Here we investigate the in situ assembly of cPcdh-γB4, a member in the γ subfamily of cPcdhs, by electron tomography and find that the full length cPcdh-γB4 does not show regular organization at the adhesion interfaces. By contrast, cPcdh-γB4 lacking the intracellular domain can generate an ordered zigzag pattern between cells and the cis-interacting mode is different from the crystal packing of the ectodomain. We also identify the residues on the ectodomain that might be important for the zigzag pattern formation by mutagenesis. Furthermore, truncation mutants of the intracellular domain reveal different assembly patterns between cell membranes, suggesting that the intracellular domain plays a crucial role in the intermembrane organization of cPcdh-γB4. Taken together, these results suggest that both ectodomain and intracellular domain regulate the in situ assembly of cPcdh-γB4 for homophilic cell adhesion, thereby providing mechanistic insights into the functional roles of cPcdhs during neuronal wiring.

Single-cell ATAC-seq technology advances our understanding of single-cell heterogeneity in gene regulation by enabling exploration of epigenetic landscapes and regulatory elements. However, low sequencing depth per cell leads to data sparsity and high dimensionality, limiting the characterization of gene regulatory elements. Here, we develop scAGDE, a single-cell chromatin accessibility model-based deep graph representation learning method that simultaneously learns representation and clustering through explicit modeling of data generation. Our evaluations demonstrated that scAGDE outperforms existing methods in cell segregation, key marker identification, and visualization across diverse datasets while mitigating dropout events and unveiling hidden chromatin-accessible regions. We find that scAGDE preferentially identifies enhancer-like regions and elucidates complex regulatory landscapes, pinpointing putative enhancers regulating the constitutive expression of CTLA4 and the transcriptional dynamics of CD8A in immune cells. When applied to human brain tissue, scAGDE successfully annotated cis-regulatory element-specified cell types and revealed functional diversity and regulatory mechanisms of glutamatergic neurons.

Polarons can naturally form in materials from the interaction of extra charge carriers with the atomic lattice. Ubiquitous, they are central to various phenomena such as high-T_c superconductivity, electrochromism, photovoltaics, photocatalysis or ion batteries. However, polaron formation remains poorly understood and mostly relies on historical models such as Landau–Pekar, Fröhlich, Holstein or Jahn–Teller polarons. Here, from advanced first-principles calculations, we show that the formation of intriguing medium-sized polarons in WO₃ does not fit with traditional models but instead arises from the local undoing of distortive atomic motions inherent to the pristine phase, which lowers the bandgap through dynamical covalency effects and drives charge trapping. We introduce the concept of the anti-distortive polaron and rationalize it from a quantum-dot model. We demonstrate that anti-distortive polarons are generic to different families of compounds and clarify how this new concept opens concrete perspectives for a better control of the polaronic state and related properties.

Accurate sister chromatid segregation requires remodeling chromosome architecture, decatenation, and attachment to the mitotic spindle. Some of these events are initiated during S-phase, but they accelerate and conclude during mitosis. Here we describe SRBD1 as a histone and nucleic acid binding protein that prevents DNA damage in interphase cells, localizes to nascent DNA during replication and the chromosome scaffold in mitosis, and is required for chromosome segregation. SRBD1 inactivation causes micronuclei, chromatin bridges, and cell death. Inactivating SRBD1 immediately prior to mitotic entry causes anaphase failure, with a reduction in topoisomerase IIα localization to mitotic chromosomes and defects in properly condensing and decatenating chromosomes. In contrast, SRBD1 is not required to complete cell division after chromosomes are condensed. Strikingly, depleting condensin II reduces the severity of the anaphase defects in SRBD1-deficient cells by restoring topoisomerase IIα localization. Thus, SRBD1 is an essential genome maintenance protein required for mitotic chromosome organization and segregation.

The Grignard reaction represents one of the most powerful carbon-carbon bond forming reactions and is the subject of continual study. Investigations of alkyl magnesium halide additions to β-hydroxy ketones identified a unique effect of the magnesium halide on diastereoselectivity, with alkylmagnesium iodide reagents demonstrating high levels of selectivity for the formation of 1,3-syn diols. Density functional theory (DFT) calculations and mechanistic studies suggest that the Lewis acidity of a chelated magnesium alkoxide can be tuned by the choice of halide, with the highest levels of diasteroselectivity achieved using alkyl magnesium iodide reagents. Exploiting this finding, we demonstrate that the diastereoselective addition of alkyl magnesium iodide reagents to ketofluorohydrins enables rapid access to naturally configured C4’-modified nucleosides. This work provides a platform to support antiviral and anticancer drug discovery and development efforts.

Self-remodeling material can change their physical properties based on mechanical environment. Recently, mechanically controlled polymerization using mechanoredox catalyst enabled composite materials to undergo a permanent structural change, thereby enhancing their mechanical strength. However, a significant delay in material’s response was observed due to the sluggish activation of the bulk catalyst for polymerization. Herein, we report a fast, mechanically controlled radical polymerization of water soluble monomers using 2D MoS₂ as the mechanoredox catalyst, studied under various mechanical stimuli, including ultrasound, ball milling and low frequency vibrations. Our strategy enables complete polymerization within several minutes of work. This accelerated process can be utilized to create composite hydrogels with the ability to alter their mechanical and electrical properties in response to mechanical stimuli. This strategy has potential for applications in smart materials such as hydrogel sensors, artificial muscles, and implantable biomaterials.

Systemic lipid homeostasis requires hepatic autophagy, a major cellular program for intracellular fat recycling. Here, we find melanocortin 3 receptor (MC3R) regulates hepatic autophagy in addition to its previously established CNS role in systemic energy partitioning and puberty. Mice with Mc3r deficiency develop obesity with hepatic triglyceride accumulation and disrupted hepatocellular autophagosome turnover. Mice with partially inactive human MC3R due to obesogenic variants demonstrate similar hepatic autophagic dysfunction. In vitro and in vivo activation of hepatic MC3R upregulates autophagy through LC3II activation, TFEB cytoplasmic-to-nuclear translocation, and subsequent downstream gene activation. MC3R-deficient hepatocytes had blunted autophagosome-lysosome docking and lipid droplet clearance. Finally, the liver-specific rescue of Mc3r was sufficient to restore hepatocellular autophagy, improve hepatocyte mitochondrial function and systemic energy expenditures, reduce adipose tissue lipid accumulation, and partially restore body weight in both male and female mice. We thus report a role for MC3R in regulating hepatic autophagy and systemic adiposity.