Journal of Genetics and Genomics

Advances in monogenic female infertility

Hao Gu, Lei Wang, et al.

doi: 10.1016/j.jgg.2025.11.009

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Complete genome assembly of the Xian rice variety IR64 as a valuable source in genomics and breeding research

Min Li, Tingting Sheng, et al.

doi: 10.1016/j.jgg.2025.11.010

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Intrinsic NPRL2 and NPRL3 regulate the sensitivity of B-cell malignancies to CAR-T cell therapy

Fuxin Han, Yuting Lu, et al.

doi: 10.1016/j.jgg.2025.11.007

Abstract (14) PDF (1)

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Although chimeric antigen receptor (CAR) T-cell therapy has markedly improved outcomes for many patients with B-cell malignancies, a subset experiences limited benefit due to primary or secondary resistance. Building on CRISPR/Cas9 genome-wide screening in malignant B-cells, we identify NPRL2 and NPRL3 as key regulators of tumor sensitivity to CAR-T cytotoxicity. This study aims to investigate the impact and mechanisms of tumor-intrinsic NPRL2 and NPRL3 on the efficacy of CAR-T cell therapy. In a tandem CD19/20 CAR-T clinical trial for relapsed/refractory (R/R) B-cell lymphoma (NCT03097770), high tumor NPRL2 or NPRL3 expression correlates with therapeutic resistance in patients. Consistently, in vitro experiments confirm that tumor cells overexpressing NPRL2/NPRL3 exhibit resistance to CAR-T–mediated cytolysis. Mechanistically, NPRL2/NPRL3 suppresses mTORC1 activity within tumor cells, negatively regulating the conjugation between tumor cells and CAR-T cells, consequently impairing CAR-T cell activation and cytotoxic function, ultimately facilitating immune escape. As therapeutic strategies, either genetic ablation of tumor-intrinsic NPRL2/NPRL3 or pharmacological activation of mTORC1 enhances CAR-T cell activation, cytotoxic degranulation, and tumor clearance both in vitro and in vivo. In conclusion, targeting tumor NPRL2/NPRL3 or directly activating mTOR represents a promising combinational strategy to potentiate CAR-T efficacy and overcome resistance in clinical practice.

Ribosomal protein bL31c interacts with translation elongation factor RAB8D to regulate chloroplast translation elongation and PSI-LHCI-LHCII assembly in Arabidopsis

Yukun Wang, Xiangsheng Ke, et al.

doi: 10.1016/j.jgg.2025.11.006

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Chloroplast translation systems have evolved specialized regulatory mechanisms distinct from those of their prokaryotic ancestors. However, critical gaps persist in understanding how these systems coordinate translation efficiency with photosynthetic apparatus assembly—a process central to plant development. Here, we identify Arabidopsis BACTERIAL LARGE RIBOSOMAL SUBUNIT PROTEIN 31 (bL31c) as a critical chloroplast ribosomal protein that interacts with the translation elongation factor RAB GTPASE HOMOLOG 8D (RAB8D) to ensure translation elongation efficiency. Knocking down bL31c disrupts chloroplast translation, causing preferential depletion of photosystem I (PSI) subunits, a functional imbalance between PSI and PSII, and paradoxical accumulation of the PSI-LHCI-LHCII supercomplex. Comparative analysis reveals evolutionary conservation of the bL31c-EF-Tu functional module in Cyanobacteria but not in E. coli, demonstrating lineage-specific adaptation of translation surveillance mechanisms. Crucially, pharmacological inhibition of translation elongation in wild-type plants phenocopies the photosystem stoichiometry defects observed in bl31c mutants, establishing defective ribosome processivity as the primary driver of photosystem imbalance. Our findings uncover a plant-specific ribosomal checkpoint mechanism that dynamically coordinates protein synthesis with photosynthetic complex assembly, providing important insights into the evolutionary rewiring of organellar gene expression systems in eukaryotes.

hfCas12Max-mediated targeted integration at accessible chromatin regions with a goat-derived UCOE enhances stable recombinant lactoferrin expression

Zhenliang Zhu, Jing Han, et al.

doi: 10.1016/j.jgg.2025.11.008

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Stable transgene expression in the mammary gland is crucial for recombinant protein production in livestock, yet it is frequently hampered by transgene silencing and random integration. To address this, we profile chromatin accessibility in goat mammary epithelial cells (GMECs) using ATAC-seq and identify 15 highly accessible genomic regions. Three of these regions are confirmed to support stable transgene expression. Notably, we identify a goat-derived ubiquitous chromatin opening element (UCOE) in the SF3B1-COQ10B intergenic region, with a high GC content (65%) and CpG island enrichment. This UCOE improves hfCas12Max-mediated integration of large DNA fragments and maintains high-level expression of human lactoferrin (hLTF) in GMECs. Subsequently, we precisely integrate the UCOE-hLTF cassette into the highly accessible loci and generate a transgenic goat via somatic cell nuclear transfer, without detectable off-target effects. Our pipeline, which integrates chromatin accessibility profiling, UCOE discovery, and precision editing, demonstrates the role of CpG island-containing UCOEs in preventing transgene silencing. The study provides valuable tools for enhancing recombinant protein production and supports the breeding of dairy goats for milk with high lactoferrin content, while advancing the understanding of the interactions between chromatin, regulatory elements, and transgenes in molecular breeding.

Genome-wide association study of HBV-related hepatocellular carcinoma identifies a functional variant at the FAM114A1 locus

Hong-Ping Yu, Bang-De Xiang, et al.

doi: 10.1016/j.jgg.2025.11.003

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Liver cancer ranks sixth in cancer incidence and third in cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the primary histological subtype, and hepatitis B virus (HBV) carriers have a higher risk of HCC. Although several susceptibility loci for HCC have been identified in East Asian populations through genome-wide association studies (GWAS), the underlying biological mechanisms of this malignancy remain incompletely understood. Here, we conduct a two-stage GWAS including 2413 cases and 2794 HBV-positive controls from a high-incidence region in Southern China. The function of the susceptibility locus is investigated by bioinformatic and experimental approaches, supported by a xenograft model. We identify a 4p14 locus significantly associated with the risk of HCC (rs55718051, OR [95% CI] = 0.73 [0.67–0.80], P_meta = 9.14 × 10^-11), and 18q23 locus with borderline significance (rs12964643: OR [95% CI] = 0.75 [0.67–0.83], P_meta = 1.11 × 10^-7). Functional experiments indicate the role of rs55718051 in FAM114A1 expression regulation, possibly through interaction of FOXA1. Knockdown of FAM114A1 significantly enhances the oncogenic phenotypes in liver cancer cells, suggesting its potential tumor suppressor role. Our findings expand the understanding of HCC susceptibility and suggest FAM114A1 as a potential suppressor in HBV-related HCC carcinogenesis.