Shoudong Ye

How embryonic stem cells (ESCs) maintain genomic integrity while sustaining self-renewal remains poorly understood. We find that transcription factor CP2-like 1 (Tfcp2l1) recruits Thrap3 in mouse ESCs, where this complex maintains RNA polymerase II activity and promotes transcription of Tfcp2l1 target genes. In addition, Thrap3 supports mESC self-renewal. Interestingly, knockdown of either Tfcp2l1 or Thrap3 induces highly overlapping alternative-splicing changes, including reduced inclusion of exon-5 in Jmjd1c. Further studies reveal that skipping of Jmjd1c exon-5 weakens the association between Jmjd1c and Mdc1, accompanied by elevated Mdc1-associated dimethylation, leading to reduced Mdc1 and Rnf8 interaction and diminished K63-linked ubiquitin signalling. These alterations impair chromatin recruitment of the Rap80 and Brca1 repair complex and increase Rad51 foci formation, indicative of a shift in DNA repair pathway preference. Accordingly, loss of Tfcp2l1 or Thrap3 results in accumulated DNA damage, hypersensitivity to genotoxic stress, compromised ESC self-renewal and enhanced apoptosis. Similar phenotypes can be recapitulated in human ESCs. Together, our findings provide new insights into how ESCs coordinate genome maintenance with self-renewal.

The genetic basis of high‐altitude hypoxia adaptation remains largely elusive, particularly the role of HBB. Here, we developed an integrative mesh‐nanorod (MN) cell sorting, chitosan nanoparticle (CS) delivery, and in vivo intraosseous (IO) injection (MN•CS•IO) system to functionally investigate HBB in cross‐species high‐altitude hypoxia adaptation. Using this MN•CS•IO platform, we transplanted high/low‐altitude species HBB‐modified lineage‐negative (Lin ⁻ ) cells into murine models, achieving 95.59% transfection efficiency and 8.15% HBB relative expression, and subjected them to simulated and natural Qinghai‐Tibet hypoxia conditions. High‐altitude HBB recipients exhibited downregulated Rragd expression, activated oxygen transport and hematopoietic lineage pathways, improved behavioral performance, and neuroprotection against hypoxia‐induced damage, compared with low‐altitude animals. MN•CS•IO system data demonstrate that HBB determines high‐altitude hypoxia adaptation. For validation, we generated bone marrow chimeras using CD45.1 hematopoietic cells with Pika‐HBB integrated at the Rosa26 locus. The reconstituted mice exhibited consistent hypoxic behavioral and phenotypic alterations with those observed via the MN•CS•IO system, validating the reliability and stability of HBB‐mediated high‐altitude hypoxia adaptation. Together, our findings demonstrate that HBB is a key genetic determinant of high‐altitude hypoxia adaptation, and also introduce a versatile gene‐function validation tool for evolutionary and biomedical research.

While significant advances have been made in maintaining stem cell pluripotency, the successful establishment of embryonic stem cells (ESCs) from various animal species in vitro remains challenging. This highlights the need for further optimization of culture conditions. Through compound library screening, we identified Danofloxacin, a small molecule, as a promoter of mouse ESC stemness. Danofloxacin enhances the formation of undifferentiated colonies and the generation of chimeric mice. Mechanistically, it suppresses HDAC1 expression and activity, resulting in increased acetylation of histone H3 at lysines 9 (H3K9ac) and 27 (H3K27ac), which in turn upregulates the expression of Tert and Prdm10 . Functional assays revealed that overexpressing Tert or Prdm10 mimics Danofloxacin's effect on ESC self‐renewal, whereas knockdown of either gene disrupts this process. Moreover, the elevated levels of H3K9ac and H3K27ac activate the PI3K/AKT and HIF‐1α signaling pathways, both of which contribute to the transcriptional upregulation of Tert and Prdm10 . These findings offer new insights into the pluripotency regulatory network and propose potential strategies for isolating ESCs from other species in vitro.

Breast cancer is the most prevalent type of malignant tumor among women. Here, we identified transcription factor CP2-like 1 (TFCP2L1) as a suppressor of breast cancer cells. Patients with breast cancer have poorer prognoses when TFCP2L1 is expressed at low levels. Consistently, the expression of TFCP2L1 is greater in normal breast tissues and cells than in breast cancer tissues and cell lines. Gain- and loss-of-function experiments and xenograft tumor assays revealed that overexpression of TFCP2L1 significantly inhibited the proliferation and migration of breast cancer cells. Conversely, the knockdown of TFCP2L1 promoted the growth and migration of breast cancer cells. Mechanistically, TFCP2L1 suppresses breast cancer progression by inhibiting the expression of glutathione peroxidase 4 ( GPX4 ), a key positive regulator of ferroptosis. Therefore, the addition of a ferroptosis inhibitor, Ferrostatin-1, can mediate the function of TFCP2L1 in breast cancer cells. On the other hand, high-throughput transcriptome sequencing revealed that TFCP2L1 negatively regulates the activity of the PI3K/AKT signaling pathway. The administration of SC79, an AKT activator, partially reversed the negative effects of TFCP2L1 on GPX4 transcription. Together, these findings indicate that TFCP2L1 functions partially by directly and indirectly regulating GPX4 -mediated ferroptosis and may serve as a potential therapeutic target for breast cancer.

While current pluripotency models capture discrete embryonic stages, they inadequately resolve transitional states during peri-implantation development. Here, we establish rosette-formative intermediate stem cells (rfISCs) from mouse embryonic stem cells using the MEK inhibitor PD0325901, the Wnt inhibitor IWR1, and the PKA activator Forskolin. These cells exhibit transcriptomic/epigenetic profiles mirroring those of E5.0‒5.5 epiblasts, bridging rosette-stage and formative pluripotency. rfISCs demonstrate developmental bipotency, retaining in vitro germline differentiation capacity while generating germline-competent chimeras in vivo. Mechanistically, we identified opposing signaling axes that govern rfISC identification through the regulation of lineage priming: IWR1 stabilizes Tcf7l1 to drive Otx2-mediated rfISC specification and neural priming, whereas Forskolin activates PKA to induce Id1-dependent neural suppression. This creates a bistable regulatory circuit in which Otx2/Id1 synergy maintains pluripotency plasticity under MEK inhibition. Notably, rfISCs can be directly derived from E5.25 epiblasts, confirming their physiological relevance. Our work bridges a fundamental gap in pluripotency modeling by capturing the RSC-to-FSC transition through dynamic signaling equilibria.

RNA-binding proteins play critical roles in RNA processing and are aberrantly expressed in colorectal cancer (CRC). Through comprehensive analysis of multiple gene expression datasets (GSE20916, GSE18105, GSE21510, TCGA-COAD and TCGA-READ), NCBP2 was identified as a potential tumorigenic gene in CRC. NCBP2 expression was significantly elevated in CRC tissues, correlated with tumour invasion and metastasis, and associated with poor patient survival outcomes. Furthermore, overexpression of NCBP2 in CRC cells was shown to increase cell proliferation, migration, and tumour invasion in both in vitro and in vivo models. Mechanistically, the NCBP2 protein stabilised LIPG mRNA via direct binding to the m7G motif in the 5’-cap structure of LIPG mRNA, thereby increasing LIPG expression. Additionally, NCBP2 promoted lipid droplet accumulation in CRC cells in a LIPG-dependent manner. These findings collectively suggest that the NCBP2-LIPG-lipid droplet axis represents a novel mechanism underlying CRC progression and metastasis, providing a promising therapeutic target for CRC treatment.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries and the development of compensatory, fragile collateral vascular networks at the skull. Emerging evidence suggests that the pathogenesis of MMD involves genetic/epigenetic predisposition, dysregulated immune responses, and environmental triggers. Notably, the RNF213 p.R4810K variant has been identified as a key genetic susceptibility factor, particularly in East Asian populations. However, the molecular mechanisms underlying disease progression remain incompletely elucidated, primarily due to the limited availability of patient-derived cerebrovascular tissues and the lack of animal models that faithfully recapitulate the full spectrum of human MMD pathology. These constraints have impeded the development of targeted therapeutic interventions. Diagnostically, digital subtraction angiography (DSA) continues to serve as the gold standard for diagnosing MMD, enabling detailed visualization of steno-occlusive lesions and characteristic moyamoya vessels. Current clinical management relies predominantly on surgical revascularization to enhance cerebral perfusion, yet this strategy does not alter the fundamental disease process. Recent advances in patient-derived vascular organoids and serum-stimulated cellular models have facilitated drug screening and biomarker identification. In this review, we provide a systematic overview of the epidemiology, clinical manifestations, and genetic landscape of MMD, with a focus on recent progress in deciphering its molecular basis. We further discuss the transformative potential of induced pluripotent stem cell (iPSC) technology, particularly when combined with CRISPR-based gene editing, for modeling MMD vasculopathy, investigating the functional impact of RNF213 mutations, and exploring precision repair approaches. These innovative approaches offer novel insights into disease mechanisms and open new avenues for therapeutic intervention in MMD.