Xin Sheng

The age-related decline in oocyte quality is a major risk factor for female infertility. Although transcriptome has been examined in aged oocytes, proteomic landscape, which reflects primary gene functional executors, remains largely unexplored. This gap limits our understanding of oocyte aging. To address this, we perform single-cell proteome/transcriptome co-profiling of GV/MII-aged oocytes from mice and humans, revealing species- and stage-specific proteomic/transcriptomic changes during oocyte aging. Strikingly, we observe uncoupled proteomic and transcriptomic alterations, indicating that proteomic changes in aged oocytes are not primarily driven by RNA levels. Furthermore, we capture molecular heterogeneity in aged oocytes and identify MCT4 as a candidate marker of oocyte aging. Functional studies suggest MCT4 contributes to aging-associated oocyte defects via lactate export, and its inhibition improves aged-oocyte quality. These findings indicate altered lactate metabolism as a candidate marker and intervention target for oocyte aging and underscore the value of our profiling in dissecting oocyte aging.

Objectives: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus with heterogeneous clinical outcomes and limited therapeutic options. Although immune dysregulation is central to LN pathogenesis, the underlying cell-type-specific regulatory mechanisms and their genetic determinants remain poorly characterized. Methods: We generated a single-cell multi-omics atlas of peripheral blood mononuclear cells (PBMCs) from newly diagnosed, minimally treated LN patients by integrating single-cell RNA-seq (scRNA-seq) and single-nucleus ATAC-seq (snATAC-seq) profiles. To elucidate genetically driven regulatory programs in a broaden LN population, we generated a blood expression quantitative trait loci (eQTL) atlas from 99 Chinese LN patients and performed Bayesian colocalization analysis to systematically prioritize putative causal genes for LN. Finally, we investigated how fine-mapped SNPs associated with LN phenotypic manifestations exert regulatory effects within distinct single-cell chromation contexts by leveraging peak-to-gene linkages at single-cell resolution. Results: Our single-cell multi-omic dataset and orthogonal analytical approaches revealed extensive immune remodeling in LN, characterized by amplified innate immune activation and impaired adaptive immune responses, and identified transcription factors (TFs) orchestrating immune regulatory circuits. Bayesian colocalization analysis nominated 14 high-fidelity causal genes for kidney function and 23 for SLE. Integration with fine-mapped GWAS variants highlighted critical cell type convergence across autoimmune disorders and immune-mediated nephropathies, particularly within B cell subsets, where TF-driven programs delineated stage-specific differentiation networks. Conclusions: Together, these analyses reconstruct the regulatory architecture underlying immune dysregulation in LN and connect genetic variation to cell-type-specific regulation, guiding genetically informed therapeutic development.

New effective early diagnosis strategies and therapeutic targets are desperately needed for high-grade serous ovarian cancer (HGSOC). Previous functional interpretation of HGSOC genome-wide association studies (GWAS) largely neglected long non-coding RNAs (lncRNAs). Here, we map genotype effects on the expression of both protein-coding genes (PCGs) and lncRNAs in 348 HGSOC tumor samples. We show that underlying genetic variants are significant drivers of expression changes for both PCGs and lncRNAs. Importantly, lncRNAs account for a higher portion of HGSOC heritability than PCGs. Bayesian colocalization analysis prioritized causal genes in HGSOC tumors and whole blood, such as ARL17A and CRHR1-IT1. Using single-nucleus transcriptome maps of HGSOC tumors generated by snRandom-seq, we characterized expression patterns of candidate susceptibility genes. Furthermore, we validated the role of CRHR1-IT1 in promoting apoptosis and inhibiting the growth of HGSOC cells. Our study provides new insights into early detection and immunotherapy development for HGSOC.

Totipotent cells (TSCs), the origin of mammalian life and foundation to early mammalian embryogenesis, are characterized by the highest differentiation capacity and extensive developmental potential. However, none of the existing embryonic databases have provided epigenetic and transcriptomic resources on totipotency, greatly limiting our understanding of the mechanisms governing the establishment and exit of totipotency. Here, we present Toti, a pioneering multi-omics database exclusively developed for totipotency, covering in vivo , in vitro and genome-edited human and mouse embryonic TSCs, TSC-like cells, pluripotent cells (PSCs), and embryos spanning preimplantation stages, with a total of 8,265 samples. Toti facilitates an in-depth exploration of the molecular mechanisms underlying totipotency by offering Search, Browse and Analysis modules available at http://toti.zju.edu.cn/ .

Key Points: We have identified a transcriptional signature of 93 genes associated with CKD severity and progression. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 gene expression is reduced in the context of more severe kidney disease and in individuals who go on to develop progressive disease. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 interacts with proteins of the cell cytoskeleton and cell-cell junctions in proximal tubule epithelial cells. Background: Currently, there are limited methods to link disease severity and risk of disease progression in CKD. To better understand this potential relationship, we interrogated the renal transcriptomic profile of individuals with CKD with measures of CKD severity and identified protein 4.1, ezrin, radixin, moesin-domain containing protein 3 (FRMD3) as a candidate gene for follow-up study. Methods: RNA-sequencing was used to profile the transcriptome of CKD biopsies from the North Dublin Renal BioBank, the results of which were correlated with clinical parameters. The potential function of FRMD3 was explored by interrogating the FRMD3 interactome and assessing the effect of lentiviral mediated FRMD3 knock down on human renal proximal tubule epithelial cells by assessing cell viability, metabolic activity, and structural markers. Results: We identified a subset of 93 genes which are significantly correlated with eGFR and percentage tubulointerstitial fibrosis at time of biopsy and with CKD progression 5 years postbiopsy. These results were validated against transcriptomic data from an external cohort of 432 nephrectomy samples. One of the top-ranking genes from this subset, FRMD3, has previously been associated with the risk of developing diabetic kidney disease. Interrogating the interactome of FRMD3 in tubule epithelial cells revealed interactions with cytoskeletal components of cell-cell junctions. Knockdown of FRMD3 expression in tubule epithelial cells resulted in increased proapoptotic activity within the cells, as well as dysregulation of E-Cadherin. Conclusions: We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this, we have identified a possible role for FRMD3 in tubule cell structure and health.