Communications Biology最新文献

Large-scale genome sequencing analyses have identified driver gene mutations (DGMs) in most cancers as well as their associated tumorigenic mechanisms. However, a small fraction of cancers are not positive for these canonical DGMs, leaving the mechanisms underpinning their formation a mystery. We hypothesized that canonical DGM-negative cancers might be driven by activation of the transcriptional coactivator YAP1 that led to the induction of epigenetic changes. To test this theory, we established a mouse mosaic model of hepatocellular carcinoma (HCC) in which we induced YAP1-TEAD activation in a few hepatocytes. Whole-exome sequencing did not identify canonical DGMs in HCCs, but bisulfite sequencing revealed widespread DNA demethylation leading to the transcriptional activation of multiple oncogenes. Knockdown of the DNA demethylation-promoting gene, Tet1, attenuated HCC formation in these mice. Single-cell spatial transcriptomics identified a Tet1-high subpopulation of HCC cells that interacted with other hepatic cell types. Our mechanistic mouse data align with the observation that YAP1-TEAD-TET1-associated signatures were also elevated in hepatocytes from patients with Fontan-associated liver disease (FALD), a condition associated with the development of HCCs with lower frequencies of canonical DGMs. Our study suggests that the YAP1-TEAD-TET1 axis promotes canonical DGM-negative HCC development, and provides new insights into the molecular processes involved.

Despite major advances in liver-on-a-chip and organoid technologies, most current in vitro liver models remain limited. Here, it is argued that these limitations are fundamentally conceptual rather than purely technical. Reverse bioengineering is introduced as a unifying design framework for liver-on-a-chip systems, in which human liver development is treated as the primary engineering blueprint rather than adult hepatic phenotype as the endpoint. Existing cell sources, liver organoids, and liver-on-a-chip platforms are critically evaluated, demonstrating that each capture complementary but incomplete aspects of liver development. Pluripotent stem cells uniquely enable access to intrinsic developmental programs and cellular diversity, organoids partially reconstruct early developmental trajectories through self-organization, and microphysiological systems provide extrinsic cues without fully encoding developmental execution. Finally, futured directions are outlined, highlighting developmentally coordinated multi-organ systems, quantitative developmental benchmarks, and the emerging role of multi-omics-enabled Digital Twins and artificial intelligence in guiding and interpreting liver-on-a-chip design.

The vertebrate brain is protected from infection by tight barriers. However, several barrier structures, including circumventricular organs, can be breached by pathogens. Here, we show that Cochlin, an extracellular matrix-binding protein with anti-bacterial properties, is produced in barrier structures and contributes to immune defence. Transcriptome analysis and in situ hybridisation indicate that cochlin is expressed in the pineal gland, area postrema, choroid plexus and discrete regions of the meninges of zebrafish, mice and humans. The protein is present in the cerebrospinal fluid, and on the surface of ventricle and meninges. Cochlin expression increases in the brain of infected animals and patients, and delivery of recombinant Cochlin reduces bacterial load in zebrafish infected with Mycobacterium marinum. Mutation of cochlin inhibits clearance of bacteria from the brain of zebrafish, and this is reversed by supplying the domain of Cochlin that is implicated in immunity. Barrier tissues thus contribute to brain defence by secreting Cochlin.

Adolescent idiopathic scoliosis is a common pediatric musculoskeletal disease that has significant impacts on childhood quality of life. Recent genome-wide association studies have identified dozens of genetic risk loci and hundreds of risk variants that primarily reside in non-coding regions of the genome. Follow up studies suggest a complex genetic architecture in which several tissues may be affected, however few causal disease variants have been identified. Here we review the functional AIS-associated variants that have been identified, how they may contribute to disease etiology, and necessary advancements that will link the effects of non-coding variants to disease mechanisms.

This study investigates how γ-tubulin and the centrosome contribute to interphase centromere dynamics and nuclear organization. Although classically associated with mitotic microtubule nucleation, here we show that γ-tubulin associates with chromatin and is enriched within centromere-defined volumes. Using live-cell imaging, immunofluorescence, and chromatin immunoprecipitation sequencing, we detect γ-tubulin-associated signal at satellite-rich, centromere-proximal chromatin. Reduced γ-tubulin levels are associated with increased centromere fluorescence intensity and reduced mobility, linking the γ-tubulin network to centromere organization. Under acute cisplatin-induced stress, centromere mobility increases, whereas centromere clustering is observed in separate fixed-cell analyses. Ser131 phosphorylation is associated with γ-tubulin self-assembly and centromere-related dynamics. Additionally, γ-tubulin accumulates in micronuclei, coinciding with increased replication-associated signal and DNA fluorescence. In primary clear cell renal cell carcinoma cells, stress is associated with higher γ-tubulin fluorescence intensity within centromere-defined volumes. Together, these findings support an association between the γ-tubulin meshwork and centromere organization, chromatin compartmentalization, and responses to genomic stress.

ATP-dependent chromatin remodeling is essential for replication, transcription, and DNA repair, especially DNA double-strand break (DSB) repair. However, the mechanisms underlying chromatin remodeling remain elusive. Here, we investigated the role of CHRAC17, a component of the chromatin assembly complex (CHRAC), in maintaining genome stability. In response to DSBs, the ISWI-family ATPase complex SNF2H-ACF1 is immediately recruited to DSBs through the H2B-type histone-fold protein CHRAC17, forming CHRAC, which promotes nucleosome assembly and recruits BRCA1 and RAD51 to the DSB site. CHRAC promotes later RAD51-mediated HR steps through additional nucleosome-remodeling activity, including nucleosome sliding activity. CHRAC17, also known as POLE3, is a subunit of DNA polymerase ε (Polε). Polε is recruited to DSBs via CHRAC17, facilitating RAD51-mediated homologous recombination (HR) and conferring resistance to PARP inhibitors. These findings define a mechanism of homologous recombination driven by coordinated regulation of nucleosome dynamics by CHRAC and Polε, thereby ensuring genome stability.

A defining feature of primates is the expansion and increased complexity of the cerebral cortex, processes that are largely associated with evolutionary adaptations of the neural progenitor-enriched outer subventricular zone (OSVZ). Yet, the genetic mechanisms underlying the emergence of the primate OSVZ remain unknown. The tree shrew is a closer outgroup to primates than rodents, its brain exhibits an intermediate phenotype; while being lissencephalic, it nonetheless possesses an OSVZ. Here, we applied laser microdissection technology to conduct comprehensive gene expression analyses of different cortical layers in the tree shrew brain across three key developmental stages. We show that cell cycle-related genes are already involved in the tree shrew OSVZ. In contrast, extracellular matrix-associated pathways appear to be unique to the primate OSVZ. Furthermore, overexpression of ZNF664 significantly increased intermediate progenitor proliferation in the mouse subventricular zone. Together, these results reveal shared molecular mechanisms underlying OSVZ development in primates and tree shrews, providing insights into the origin of primate cortical complexity.

The long-term resilience of the Southern Ocean ecosystem relies on healthy populations of Antarctic krill, but climate change and increasing fishing pressure are placing this species at risk. Protecting Antarctic krill requires identification of key habitats for critical life history stages. Here, we present multiple lines of evidence that reproductively active female Antarctic krill utilize deep-sea hydrothermal vent habitats. Gravid females collected at Hook Ridge (Bransfield Strait) bore paired spermatophores and exhibited stable isotope signatures, microbial gut communities, and trace-metal profiles consistent with direct consumption of chemosynthetic microbes and prior visitation to vent sites. Complementary ROV footage from Quest Caldera (Scotia Arc) confirms that such vent use is not isolated. Collectively, our findings reveal a previously unrecognized role of vent habitats in the ecology of one of the Southern Ocean's most ecologically critical taxa and highlight the importance of incorporating vent-associated regions into marine protected area planning.