Single-cell sequencing is frequently affected by “omission” due to limitations in sequencing throughput, yet bulk RNA-seq may contain these ostensibly “omitted” cells. Here, we introduce the single cell trajectory blending from Bulk RNA-seq (BulkTrajBlend) algorithm, a component of the OmicVerse suite that leverages a Beta-Variational AutoEncoder for data deconvolution and graph neural networks for the discovery of overlapping communities. This approach effectively interpolates and restores the continuity of “omitted” cells within single-cell RNA sequencing datasets. Furthermore, OmicVerse provides an extensive toolkit for both bulk and single cell RNA-seq analysis, offering seamless access to diverse methodologies, streamlining computational processes, fostering exquisite data visualization, and facilitating the extraction of significant biological insights to advance scientific research.

Cancer cells become immortalized through telomere maintenance mechanisms, such as telomerase reverse transcriptase (TERT) activation. In addition to maintaining telomere length, TERT activates manifold cell survival signaling pathways. However, telomerase-associated gene signatures in cancer remain elusive. We performed a systematic analysis of TERT high (TERThigh) and low (TERTlow) cancers using multidimensional data from The Cancer Genome Atlas (TCGA). Multidimensional data were analyzed by propensity score matching weight algorithm. Coexpression networks were constructed by weight gene coexpression network analysis (WGCNA). Random forest classifiers were generated to identify cancer subtypes. The TERThigh-specific mRNA expression signature is associated with cell cycle-related coexpression modules across cancer types. Experimental screening of hub genes in the cell cycle module suggested TPX2 and EXO1 as potential regulators of telomerase activity and cell survival. MiRNA analysis revealed that the TERThigh-specific miR-17-92 cluster can target biological processes enriched in TERTlow cancer and that its expression is negatively correlated with the tumor/normal telomere length ratio. Intriguingly, TERThigh cancers tend to have mutations in extracellular matrix organization genes and amplify MAPK signaling. By mining the clinical actionable gene database, we uncovered a number of TERThigh-specific somatic mutations, amplifications and high expression genes containing therapeutic targets. Finally, a random forest classifier integrating telomerase-associated multi-omics signatures identifies two cancer subtypes showed profound differences in telomerase activity and patient survival. In summary, our results depict a telomerase-associated molecular landscape in cancers and provide therapeutic opportunities for cancer treatment.

The majority of the human genome encodes long noncoding RNA (lncRNA) genes, critical regulators of various cellular processes, which largely outnumber protein-coding genes. However, lncRNA-involved fusions have not been surveyed and characterized yet. Here, we present a systematic study of the lncRNA fusion landscape across cancer types and identify >30 000 high-confidence tumor-specific lncRNA fusions (using 8284 tumor and 6946 normal samples). Fusions positively correlated with DNA damage and cancer stemness and were specifically low in microsatellite instable (MSI)-High or virus-infected tumors. Moreover, fusions distribute differently among cancer molecular subtypes, but with shared enrichment in tumors that are microsatellite stable (MSS), with high somatic copy number alterations (SCNA), and with poor survival. Importantly, we find a potentially new mechanism, mediated by enhancer RNAs (eRNA), which generates secondary fusions that form densely connected fusion networks with many fusion hubs targeted by FDA-approved drugs. Finally, we experimentally validate functions of two tumor-promoting chimeric proteins derived from mRNA-lncRNA fusions, KDM4B–G039927 and EPS15L1–lncOR7C2–1. The EPS15L1 fusion protein may regulate (Gasdermin E) GSDME, critical in pyroptosis and anti-tumor immunity. Our study completes the fusion landscape in cancers, sheds light on fusion mechanisms, and enriches lncRNA functions in tumorigenesis and cancer progression.

The accumulating evidence demonstrates that the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. In particular, the APOBEC3 family was shown to induce tumor mutations by an aberrant DNA editing mechanism. However, knowledge regarding the reconstitution of the APOBEC family genes across cancer types is still lacking. Here, we systematically analyzed the molecular alterations, immuno-oncological features, and clinical relevance of the APOBEC family in pan-cancer. We found that APOBEC genes were widely and significantly differentially expressed between normal and cancer samples in 16 cancer types, and that their expression levels are significantly correlated with the prognostic value in 17 cancer types. Moreover, two patterns of APOBEC-mediated stratification with distinct immune characteristics were identified in different cancer types, respectively. In ACC, for example, the first pattern of APOBEC-mediated stratification was closely correlated with the phenotype of immune activation, which was characterized by a high immune score, increased infiltration of CD8 T cells, and higher survival. The other pattern of APOBEC-mediated stratification was closely correlated with the low-infiltration immune phenotype, which was characterized by a low immune score, lack of effective immune infiltration, and poorer survival. Further, we found the APOBEC-mediated pattern with low-infiltration immune was also highly associated with the advanced tumor subtype and the CIMP-high tumor subtype (CpG island hypermethylation). Patients with the APOBEC-mediated pattern with immune activation were more likely to have therapeutic advantages in ICB (immunological checkpoint blockade) treatment. Overall, our results provide a valuable resource that will be useful in guiding oncologic and therapeutic analyses of the role of APOBEC family in cancer.

Bivalves are species-rich mollusks with prominent protective roles in coastal ecosystems. Across these ancient lineages, colony-founding larvae anchor themselves either by byssus production or by cemented attachment. The latter mode of sessile life is strongly molded by left-right shell asymmetry during larval development of Ostreoida oysters such as Crassostrea hongkongensis. Here, we sequenced the genome of C. hongkongensis in high resolution and compared it to reference bivalve genomes to unveil genomic determinants driving cemented attachment and shell asymmetry. Importantly, loss of the homeobox gene Antennapedia (Antp) and broad expansion of lineage-specific extracellular gene families are implicated in a shift from byssal to cemented attachment in bivalves. Comparative transcriptomic analysis shows a conspicuous divergence between left-right asymmetrical C. hongkongensis and symmetrical Pinctada fucata in their expression profiles. Especially, a couple of orthologous transcription factor genes and lineage-specific shell-related gene families including that encoding tyrosinases are elevated, and may cooperatively govern asymmetrical shell formation in Ostreoida oysters.