A comprehensive transcriptomic survey of pigs can provide a mechanistic understanding of tissue specialization processes underlying economically valuable traits and accelerate their use as a biomedical model. Here we characterize four transcript types (lncRNAs, TUCPs, miRNAs, and circRNAs) and protein-coding genes in 31 adult pig tissues and two cell lines. We uncover the transcriptomic variability among 47 skeletal muscles, and six adipose depots linked to their different origins, metabolism, cell composition, physical activity, and mitochondrial pathways. We perform comparative analysis of the transcriptomes of seven tissues from pigs and nine other vertebrates to reveal that evolutionary divergence in transcription potentially contributes to lineage-specific biology. Long-range promoter–enhancer interaction analysis in subcutaneous adipose tissues across species suggests evolutionarily stable transcription patterns likely attributable to redundant enhancers buffering gene expression patterns against perturbations, thereby conferring robustness during speciation. This study can facilitate adoption of the pig as a biomedical model for human biology and disease and uncovers the molecular bases of valuable traits.
Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front β-sheet strands. The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4. Though ipilimumab binds to the same epitope with tremelimumab on CTLA-4 with similar binding affinity, the higher dissociation rate of ipilimumab may indicate the dynamic binding to CTLA-4, which may affect its pharmacokinetics. The molecular basis of ipilimumab-based anti-CTLA-4 blockade and comparative study of the binding characteristics of ipilimumab and tremelimumab would shed light for the discovery of small molecular inhibitors and structure-based monoclonal antibody optimization or new biologics.
Pig epiblast-derived pluripotent stem cells are considered to have great potential and broad prospects for human therapeutic model development and livestock breeding. Despite ongoing attempts since the 1990s, no stably defined pig epiblast-derived stem cell line has been established. Here, guided by insights from a large-scale single-cell transcriptome analysis of pig embryos from embryonic day (E) 0 to E14, specifically, the tracing of pluripotency changes during epiblast development, we developed an in vitro culture medium for establishing and maintaining stable pluripotent stem cell lines from pig E10 pregastrulation epiblasts (pgEpiSCs). Enabled by chemical inhibition of WNT-related signaling in combination with growth factors in the FGF/ERK, JAK/STAT3, and Activin/Nodal pathways, pgEpiSCs maintain their pluripotency transcriptome features, similar to those of E10 epiblast cells, and normal karyotypes after more than 240 passages and have the potential to differentiate into three germ layers. Strikingly, ultradeep in situ Hi-C analysis revealed functional impacts of chromatin 3D-spatial associations on the transcriptional regulation of pluripotency marker genes in pgEpiSCs. In practice, we confirmed that pgEpiSCs readily tolerate at least three rounds of successive gene editing and generated cloned gene-edited live piglets. Our findings deliver on the long-anticipated promise of pig pluripotent stem cells and open new avenues for biological research, animal husbandry, and regenerative biomedicine.
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