华大基因

Terpene is an important secondary metabolite during plant development. The gene family of terpene synthases (TPS) is in charge of producing thousands of different terpenes that can increase the environmental fitness of plant. Some types of terpene contribute aroma and flavor that influence consumer preferences in tobacco but the knowledge of the TPS genes encoded by local tobacco cultivars are limited. Here, a total of 186 TPS genes were identified by annotating the tobacco genome sequences. Phylogenetic analysis showed that a few tobacco-exclusive TPS clades emerged recently through gene duplication, which are likely to be responsible for a range of compounds that separate N. tabacum cultivars from its wild relatives. Transcriptome sequencing of two local cultivars at three developmental stages revealed that five TPS genes from the TPS-a and TPS-b lineages are constitutively expressed while other duplicated ones are only expressed at the time of harvest. Additionally, some TPS genes underwent alternative splicing, which further diversified the protein sequences of the TPS gene family. The expression diversity and the evolution dynamics of this important gene family highlighted its critical role in the plant of tobacco. Our study provided candidate gene target for future breeding improvement of this critical industrial crop.

Abstract We present HiChew, a novel chromatin conformation capture method combining efficient sticky-end ligation with post-PCR methylation-based enrichment. HiChew achieves approximately 50% valid pair ratios compared to 8% for unenriched methods, while maintaining high sensitivity. Its single-cell implementation, snHiChew, achieves 45–50% valid pair ratios, and enables 5–10 kb resolution mapping with 70–80% bin coverage. Comparative analyses show strong concordance with conventional Hi-C for chromatin compartments, TADs, and loops. By combining scalability, cost-effectiveness and data quality, HiChew provides a powerful platform for advancing studies of 3D genome architecture analysis.

To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-β-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the βIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.

Cancer-associated fibroblasts (CAFs) are major stromal components of the tumor microenvironment, yet how their metabolic states shift during therapy and influence anti-tumor immunity remains unclear. By integrating clinical cancer samples, single-cell RNA analyses, and functional studies, we identify a chemotherapy-conditioned PTGER3+ CAF subset characterized by enhanced lipid oxidation. This metabolic reprogramming strengthens antitumor immunity by promoting CD8+ T cell activation and cytotoxicity through the suppression of PTEN-related signaling. Clinically, higher proportions of therapy-induced PTGER3+ CAFs correlate with improved treatment responses and better patient prognosis. Together, these findings reveal a previously unrecognized stromal metabolic adaptation that supports CD8+ T cell immunity and highlight CAF-driven lipid oxidation and its regulation of CD8+ T cell PTEN signaling as potential avenues to enhance chemotherapy and immunotherapy efficacy.

Human peripheral blood exhibits molecular and cellular heterogeneity across populations, yet the underlying mechanisms remain unclear. We present the Chinese Immune Multi-Omics Atlas (CIMA), characterizing molecular variations linked to sex, age, and genetic variants through multi-omics analysis of more than 10 million circulating immune cells from 428 Chinese adults. CIMA established an enhancer-driven gene regulatory network comprising 237 robust regulons; identified 9600 eGenes and 52,361 caPeaks at cell type resolution; and revealed pleiotropic associations among immune-related disease risk loci, cis-expression quantitative trait loci (QTLs), and chromatin accessibility QTLs. Furthermore, the cell language model CIMA-CLM predicted chromatin accessibility and evaluated the effects of noncoding variants from chromatin sequences and gene expression. CIMA provides a comprehensive reference for immune-related disease research.