Biology subjects

Liu, S.-Y.

Publications and source records attributed to Liu, S.-Y..

6 recordsLinked to original sources

bioRxiv2026

DHX36 regulates antral follicle development and ovulation as a non-OSF maternal factor by maintaining oocyte homeostasis and supporting OSF delivery

Healthy ovarian follicle development and ovulation require coordinated communication between oocytes and surrounding somatic cells. Although oocyte-secreted factors (OSFs), such as GDF-9 and BMP-15, are established regulators of this communication, the non-OSF maternal factors that support OSF delivery and signaling during late-stage follicle development remain poorly understood. Here, using an oocyte-specific Dhx36 knockout mouse model, we identify the G-quadruplex (G4) helicase DHX36 as a non-OSF maternal factor required for antral follicle development and hormone-induced ovulation. Dhx36 deficiency caused severe defects in granulosa cell proliferation and cumulus expansion, accompanied by impaired activation of SMAD2/3 and SMAD1/5/8, while ERK1/2 activation remained intact. Although the expression of major OSFs was largely unchanged, Dhx36-deficient oocytes exhibited disrupted microvilli and transzonal projections (TZPs), resulting in defective OSF delivery and impaired oocyte-cumulus communication. Proteomic, lipidomic, and ultrastructural analyses further revealed dysregulated phospholipid metabolism, membrane organization, autophagy, and organelle homeostasis, including abnormal lysosomal, mitochondrial, and endoplasmic reticulum structures. Integrative transcriptomic and proteomic analyses identified concordant downregulation of genes involved in these processes, whose promoters were enriched in potential G4 motifs. Consistently, Dhx36 deficiency was associated with reduced RNA polymerase II activity, while pharmacological G4 stabilization impaired transcription of selected genes. Together, these findings establish DHX36 as a maternal regulator that links oocyte intrinsic homeostasis to intercellular communication, suggesting that DHX36-dependent maintenance of membrane and organelle integrity is essential for OSF delivery, cumulus cell function, antral follicle development, and ovulation.

developmental biology↗

bioRxiv2024

Novel naphthyridones targeting Pannexin 1 for colitis management

Pannexin 1 (PANX1) forms cell-surface channels capable of releasing signaling metabolites for diverse patho-physiological processes. While inhibiting dysregulated PANX1 is proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, we performed hit-to-lead optimization and identified a naphthyridone, compound 12, as a new PANX1 inhibitor with an IC50 of 0.73 M that does not affect pannexin-homologous LRRC8/SWELL1 channels. Using structure-activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, we revealed that compound 12 directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, we found that compound 12 markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof-of-concept treatment for IBD. These data describe the mechanism of action for a new PANX1 inhibitor, identify the binding site for future drug design, and present a targeted strategy for treating IBD. TeaserA specific PANX1 inhibitor presents a proof-of-concept treatment for inflammatory bowel disease.

molecular biology↗

bioRxiv2024

N-acetyltransferase 10-mediated mRNA N4-acetylation is Essential for the Translational Regulation During Oocyte Meiotic Maturation in Mice

Mammalian oocyte maturation is driven by the strict translational regulation of maternal mRNAs stored in the cytoplasm. However, the function and mechanism of post-transcriptional chemical modifications, especially the newly identified N4-acetylcytidine (ac4C) modification catalyzed by N-acetyltransferase 10 (NAT10), are unknown. In this study, we developed a low-input ac4C sequencing technology, ac4C LACE-seq, and mapped 8241 ac4C peaks at the whole-transcriptome level using 50 mouse oocytes at the germinal vesicle stage. We profiled the mRNA landscapes of NAT10-interactions and ac4C modifications. The NAT10-interacted and ac4C-modified transcripts are associated with high translation efficiency in oocytes. Oocyte-specific Nat10 knockout wiped out ac4C signals in oocytes and caused severe defects in meiotic maturation and female infertility. ac4C LACE-seq results indicated that Nat10 deletion led to a failure of ac4C deposition on mRNAs encoding key maternal factors, such as MSY2, ZAR1, BTG4, and cyclin B1, which regulate transcriptome stability and maternal-to-zygotic transition. Nat10-deleted oocytes showed decreased mRNA translation efficiency during meiotic maturation, partially due to the direct inhibition of ac4C sites on specific transcripts. In summary, we developed a low-input, high-sensitivity mRNA ac4C profiling approach and highlighted the important physiological function of ac4C in the precise regulation of oocyte meiotic maturation by enhancing translation efficiency.

developmental biology↗

bioRxiv2022

Dissecting the contributions of tumor heterogeneity on metastasis at single-cell resolution

Metastasis is the leading cause of cancer-related deaths, but metastasis research is challenged by limited access to patient material and a lack of experimental models that appropriately recapitulate tumor heterogeneity. Here, we analyzed single-cell transcriptomes of matched primary tumor and metastasis from patient-derived xenograft models of breast cancer, demonstrating that primary tumor and metastatic cells show profound transcriptional differences across heterogeneous tumors. While primary tumor cells upregulated several metabolic genes, metastatic cells displayed a motility phenotype in micrometastatic lesions and increased stress response signaling during metastatic progression. Additionally, we identified gene signatures that are associated with the metastatic potential and correlated with patient outcomes. Poorly metastatic primary tumors showed increased immune-regulatory control that may prevent metastasis, whereas highly metastatic primary tumors upregulated markers of epithelial-mesenchymal transition (EMT). We found that intra-tumor heterogeneity is dominated by epithelial-mesenchymal plasticity (EMP) which presented as a dynamic continuum with intermediate cell states that were characterized by novel, specific markers. These intermediate EMP markers correlated with worse patient outcomes and could serve as potential new therapeutic targets to block metastatic development.

cancer biology↗

bioRxiv2019

Mechanistic and compositional studies of the autophagy-inducing areca nut ingredient

Areca nut (AN) is a popular chewing carcinogen worldwide causing a variety of diseases such as oral and esophageal carcinomas. We previously found that the partially purified 30-100 kDa fraction of AN extract (ANE 30-100K) induces autophagy in oral carcinoma OECM-1 cells and some other different types of cells. Since autophagy is known to play important roles in tumor establishment and development, the underlying mechanisms of ANE 30-100K-induced autophagy (AIA) is worthy of further investigation. In this study, we further demonstrated that the cytotoxic concentration of ANE 30-100K induces some typical autophagy hallmarks in esophageal carcinoma (CE81T/VGH) cells in an Atg5-dependent manner. Furthermore, the endocytosis inhibitor (methyl-{beta}-cyclodextrin) and two caveolin shRNAs, as well as two proteasome inhibitors (lactacystin and epoxomicin), were shown to attenuate ANE 30-100K-induced cytotoxicity and LC3-II accumulation significantly in OECM-1 and CE81T/VGH cells. Finally, we also analyzed the carbohydrate compositions of ANE 30-100K by phenol-sulfuric acid method and high performance anion exchange chromatography with pulse amperic detector. The results showed that ANE 30-100K contains about 67% carbohydrate and is composed of fucose (5.938%), arabinose (24.631%), glucosamine (8.066%), galactose (26.820%), glucose (21.388%), and mannose (13.157%). Collectively, these results suggest that caveolin-mediated endocytosis and proteasome are required for AIA and the major components of ANE 30-100K are carbohydrates. This study may have provided new knowledges of the action mechanisms and compositions of ANE 30-100K.

cancer biology↗

bioRxiv2017

Cryptic phylogeographic history sheds light on the generation of species diversity in sky-island mountains

Biodiversity hotspots should be given high priority for conservation under the situation of global climate change. The sky islands in southwestern China are characterized by extraordinarily high species diversity and are among one of the worlds top biodiversity hotspots. However, neither the actual species diversity in this region or mechanisms generating this diversity are well explored. Here, we report on the phylogeographic analysis of the long-tailed mole (Scaptonyx fusicaudus), a semi-fossorial mammal that inhabits the montane cool forests across the Chinese sky islands and is considered to represent one species divided into two subspecies. Analyses using DNA sequence data from one mitochondrial and six nuclear genes revealed that populations inhabiting different mountains exhibited exceptionally strong geographic structure. The lowlands and large rivers act as \"soft\" and \"hard\" barriers to dispersal, respectively, isolating evolutionary lineages for up to 11 million years. Our results suggest that the mountain ranges act as interglacial refugia buffering populations from climate fluctuations, further facilitating allopatric diversification. Strikingly, species delimitation analyses suggests that the long-tailed mole may comprise 18 operational taxonomic units and 17 putative species. Our results suggest that for low-vagility species, the complex topography of the Chinese sky islands has shaped genetic diversity and structure and promoted exceptional diversification through a combination of eco-environmental stability as well as geographic fragmentation. The patterns observed in S. fusicaudus may be representative for other cold- adapted species, reflecting the generation of mammalian faunal diversity in the sky-island mountains of southwestern China.

zoology↗