Biology subjects

Sun, Q.-Y.

Publications and source records attributed to Sun, Q.-Y..

10 recordsLinked to original sources

bioRxiv2024

Maternal total sleep deprivation causes oxidative stress and mitochondrial dysfunction in oocytes associated with fertility decline in mice

Previous studies have shown sleep deprivation has an impact on several aspects of health and disease. Sleep deprivation suppresses melatonin production and excessive HPA activation in women, which may reduce the chances of fertility. However, little is known about how and by what relevant mechanisms it affects female fertility. In this study, female mice underwent 72 hours of total sleep deprivation (TSD) caused by rotating wheel or 2 different controls: a stationary wheel, or forced movement at night. Even though, there was no evident anomaly of natural ovulation, the TSD female mice showed impaired early embryo development . Overall levels of estrogen and FSH were lower throughout the estrus cycle (especially in proestrus). RNA Sequencing (RNA-Seq) was used to discover differentially expressed genes (DEGs) that might be involved in oocyte quality after TSD. A total of 42 genes showed significant differential expression in GV oocytes after TSD. These included genes such as Usmg5, Atp5k, Ccnd2 and Tpm3, which were enriched in gene ontology terms of mitochondrial protein complex, oxidoreductase activity, cell division, cell cycle G1/S phase transition, as well as others. The increased concentrations of reactive oxygen species (ROS) in germinal vesicle (GV) and metaphase II (MII) oocytes from TSD mice were observed, which might be induced by impaired mitochondrial function caused by TSD. The GV oocytes displayed increased mitochondrial DNA (mtDNA) copy number and a significant transient increase in inner mitochondrial membrane potential ({bigtriangleup}{psi}m) from the TSD mice probably due to compensatory effect. In contrast, MII oocytes in the TSD group showed a decrease in the mtDNA copy number and a lower {bigtriangleup} {psi}m compared with the controls. Furthermore, abnormal distribution of mitochondria in the GV and MII oocytes was also observed in TSD mice, suggesting mitochondrial dysfunction. In addition, abnormal spindle and abnormal arrangement of chromosomes in MII oocytes were markedly increased in the TSD mice compared with the control mice. In conclusion, our results suggest that TSD significantly alters the oocyte transcriptome, contributing to oxidative stress and disrupted mitochondrial function, which then resulted in oocyte defects and impaired early embryo development in female mice.

developmental biology↗

bioRxiv2024

Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs

Maternal obesity has deleterious effects on the process of establishing oocyte DNA methylation; yet the underlying mechanisms remain unclear. In the present study, we found that maternal obesity induced by high-fat diet (HFD) disrupted the genomic methylation of oocytes, and that at least a part of the altered DNA methylation was transmitted to the F2 oocytes and the livers via females. We further examined the metabolome of serum and found that the altered metabolites such as melatonin may play a key role in the disrupted genomic methylation in the oocytes of obese mice. We further found that exogenous melatonin treatment significantly reduced the hyper-methylation of HFD oocytes, and the increased expression of DNMT3a and DNMT1 in HFD oocytes was also decreased. To address how melatonin regulates the expression of DNMTs, the function of melatonin was inhibited or activated upon oocytes. Results revealed that melatonin may regulate the expression of DNMTs via the cAMP/PKA/CREB pathway. These results suggest that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway.

developmental biology↗

bioRxiv2023

Spatiotemporal and single-cell atlas to dissect cell lineage differentiation and regional specific cell types in mouse ovary morphogenesis

Characterization of cell heterogeneity and molecular diversity using single-cell RNA sequencing has greatly enhanced our understanding of the ovarys dynamic differentiation processes. However, regional specification of ovarian cells for certain physiological functions remains largely unexplored in the physical space. Here, we combine spatial transcriptomics with single-cell RNA sequencing technologies to build a spatiotemporal and single-cell atlas of ovaries from fetal to adult stages. We construct the pseudotime trajectories of female germ cells and bipotential pregranulosa cells and define key regulatory transcription factors responsible for their differentiation processes. Specifically, we dissect the relationships between two waves of meiosis initiation, oogenesis processes and folliculogenesis. Moreover, we characterize the region-specific subtypes of granulosa cells and luteal cells and construct pseudo-space-time trajectories from granulosa cells to luteal cells. Notably, we identify small luteal cells, a novel cell type, which highly express Onecut2 and exclusively locate at the corpus luteum. Altogether, this study comprehensively delineates ovary development and regional specific ovarian cell types.

developmental biology↗

bioRxiv2021

Gut-testis axis: microbiota-(n-3) PUFA improving semen quality in type 1 diabetes

Gut dysbiosis and type 1 diabetes (T1D) are closely related, and gut dysbiosis and male infertility are correlated, too. Moreover, most male T1D patients are of active reproductive age. Therefore, it is crucial to explore possible means for improving their semen quality. Here, we found that fecal microbiota transplantation (FMT) from alginate oligosaccharide (AOS) improved gut microbiota (A10-FMT) significantly decreased blood glucose and glycogen, and increased semen quality in streptozotocin-induced T1D subjects. A10-FMT improved T1D-disturbed gut microbiota, especially the increase in small intestinal lactobacillus, and blood and testicular metabolome to produce n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to ameliorate spermatogenesis and semen quality. Moreover, A10-FMT can improve spleen and liver function to strengthen the systemic environment for sperm development. FMT from gut microbiota of control animals (Con-FMT) produced some beneficial effects; however, to a smaller extent. Thus, AOS improved gut microbiota may be a useful protocol for improving semen quality and male fertility in T1D patients. ImportanceClinical data suggest that male reproductive dysfunction especially infertility is a critical issue for type 1 diabetic patient (T1D) because most of them are at the reproductive age. Gut dysbiosis is involved in T1D related male infertility. However, improved gut microbiota can be used to improve spermatogenesis and male fertility in T1D remains incompletely understood. We discovered that alginate oligosaccharide-improved gut microbiota (A10-FMT) significantly ameliorated spermatogenesis and semen quality. AOS-improved gut microbiota (specific microbes) may serve as a novel, promising therapeutic approach for the improvement of semen quality and male fertility in T1D patients.

developmental biology↗

bioRxiv2020

Lapatinib protects against epileptic seizures via halting glutathione peroxidase 4-dependent ferroptosis

Background and PurposeRepetitive epileptic seizures trigger massive neuronal death. Therefore, neuroprotection plays a role in preventing neuronal death and inversely suppresses seizure generation. Additionally, some studies have shown ferroptosis, featured by lipid peroxidation (a dominant form of oxidative stress in the brain), is of paramount importance in epileptic seizures. Lapatinib can play a first-line anti-tumor role by targeting oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. We hypothesize whether lapatinib can protect against ferroptosis in epileptic seizures via regulating lipid peroxidation. Experimental ApproachThe epileptic behavior of the mice was recorded after intracranial injection of KA. Western blot and RT-qPCR were used to detect the protein expression of 4-hydroxynonenal (4-HNE) and glutathione peroxidase 4 (GPX4) and the mRNA expression of prostaglandin endoperoxide synthase 2 (PTGS2) in vivo and in vitro. The level of lipid reactive oxygen species (lipid ROS) in cells pretreated with lapatinib was analyzed by flow cytometry. Key ResultsLapatinib remarkably prevented KA-induced epileptic seizures in mice and ferroptosis was involved in the neuroprotection of lapatinib. Compared with the model group, western blot showed that lapatinib significantly upregulated the levels of GPX4. In the ferroptotic cell death model, lapatinib exerted neuroprotection via up-regulating GPX4. Treatment with Ras-selective lethal small molecule 3 (RSL3), a selective GPX4 inhibitor abrogated its anti-ferroptotic potential. Conclusions and ImplicationsThese results illustrated that lapatinib has neuroprotective potential against KA-triggered epileptic seizures via suppressing GPX4-dependent ferroptosis. What is already knownO_LIActivation of ferroptosis occurs in epileptic seizures. C_LI What this study addsO_LILapatinib protects brain against epileptic seizures via blocking ferroptosis. C_LIO_LIGPX4-dependent ferroptosis is involved in the neuroprotection of lapatinib. C_LI What is the clinical significanceO_LIInhibition of ferroptosis by lapatinib represents a potential neuroprotective strategy for epileptic patients. C_LI

neuroscience↗

bioRxiv2020

Single cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Germ cells are vital for reproduction and heredity. However, the mechanisms underlying female germ cell development in primates, especially in late embryonic stages, remain elusive. Here, we performed single-cell RNA sequencing of 12471 cells from whole fetal ovaries, and explored the communications between germ cells and niche cells. We depicted the two waves of oogenesis at single cell resolution and demonstrated that progenitor theca cells exhibit similar characteristics to Leydig cells in fetal monkey ovaries. Notably, we found that ZGLP1 displays differentially expressed patterns between mouse and monkey, which is not overlapped with NANOG in monkey germ cells, suggesting its role in meiosis entry but not in activating oogenic program in primates. Furthermore, the majority of germ cell clusters that highly expressed PRDM9 and SPO11 might undergo apoptosis after cyst breakdown, leading to germ cell attrition. Overall, our work provides new insights into the molecular and cellular basis of primate fetal ovary development at single-cell resolution.

developmental biology↗

bioRxiv2020

Single cell RNA sequencing reveals the landscape of early female germ cell development

Female germ cell development consists of complex events including sex determination, meiosis initiation, retardation and resumption. During early oogenesis, the asynchrony of the transition from mitosis to meiosis results in heterogeneity in the female germ cell populations at a certain embryonic stage, which limits the studies of meiosis initiation and progression at a higher resolution level. Here, we investigated the transcriptional profiles of 19363 single germ cells collected from E12.5, E14.5 and E16.5 mouse fetal ovaries. Clustering analysis identified seven groups and defined dozens of corresponding transcription factors, providing a global view of cellular differentiation from primordial germ cells towards meiocytes. Further, we explored the dynamics of gene expression within the developmental trajectory with special focus on the mechanisms underlying meiotic initiation. We found that Dpy30 may be involved in the regulation of meiosis initiation at the epigenetic level. Our data provide key insights into the transcriptome features of peri-meiotic female germ cells, which offers new information not only on meiosis initiation and progression but also on screening pathogenic mutations in meiosis-associated diseases.

developmental biology↗

bioRxiv2019

Lysyl oxidase promotes neuronal ferroptosis exacerbating seizure-induced hippocampal damage

Epilepsy is a serious neurological disorder and characterized by recurrent and unprovoked seizures. A critical pathological factor in the seizure genesis is neuronal loss. However, mechanisms which lead to neuronal death remain elusive. Our present investigation depicted that ferroptosis, a recently discovered iron- and lipid peroxidation-dependent cell death, probably served as a mechanism in murine models of kainic acid (KA)-induced seizures. And treatment with ferroptosis inhibitors ferrostatin-1 (Fer-1), liproxstatin-1 (Lipo-1) or deferoxamine (DFO) significantly suppressed seizure severity and frequency. Using gene expression profiling in HT22 cells after glutamate exposure (a validated ferroptotic cell death model), we identified lysyl oxidase (Lox) as a novel inducer of ferroptosis. Mechanistically, Lox promoted ferroptosis via activation of extracellular regulated protein kinase (ERK)-dependent 5-lipoxygenase (Alox5) phosphorylation at serine 663 residue signaling, subsequent leading to lipid reactive oxygen species (ROS) accumulation. In a murine model of KA-induced seizure, we illustrated that administration of {beta}-aminopropionitrile (BAPN), a specific Lox inhibitor, remarkably prevented seizure generation. Overall, these findings highlight Lox, a novel identified ferroptotic regulator in neurons, serves as a potential target for seizure-related disease including epilepsy.

neuroscience↗

bioRxiv2019

CDC6 regulates both G2/M transition and metaphase-to-anaphase transition during the first meiosis of mouse oocytes

Cell division cycle protein CDC6 is essential for the initiation of DNA replication. CDC6 was recently shown to inhibit the microtubule-organizing activity of the centrosome. Here, we show that CDC6 is localized to the spindle from Pro-MI to MII stages of oocytes, and it plays important roles at two critical steps of oocyte meiotic maturation. CDC6 depletion facilitated the G2/M transition (GV breakdown, GVBD) through regulation of Cdh1 and cyclin B1 expression and CDK1 phosphorylation in a GVBD-inhibiting culture system containing milrinone. Furthermore, GVBD was significantly decreased after knockdown of cyclin B1 in CDC6-depleted oocytes, indicating that the effect of CDC6 loss on GVBD stimulation was mediated, at least in part, by raising cyclin B1. Knockdown of CDC6 also caused abnormal localization of {gamma}-tubulin, resulting in defective spindles, misaligned chromosomes, cyclin B1 accumulation and spindle assembly checkpoint (SAC) activation, leading to significant Pro-MI/MI arrest and PB1 extrusion failure. These phenotypes were also confirmed by time-lapse live cell imaging analysis. The results indicate that CDC6 is indispensable for maintaining G2 arrest of meiosis and functions in G2/M checkpoint regulation in mouse oocytes. Moreover, CDC6 is also a key player regulating meiotic spindle assembly and metaphase-to-anaphase transition in meiotic oocytes.\n\nSummary statementWe show that CDC6 is indispensable for maintaining G2 arrest of mouse oocytes. Moreover, CDC6 is also a key player regulating meiotic spindle assembly and metaphase-to-anaphase transition in meiotic oocytes.

developmental biology↗

bioRxiv2018

Mettl14 is required for mouse post-implantation development by facilitating epiblast maturation

N6-methyladenosine (m6A) is the most prevalent and reversible internal modification of mammalian messenger and noncoding RNAs mediated by specific m6A writer, reader, and eraser proteins. As an m6A writer, the METTL3-METTL14-WTAP complex dynamically regulates m6A modification and plays important roles in diverse biological processes. However, our knowledge about the complete functions of this RNA methyltransferase complex, the contributions of each component to the methylation and their impacts on different biological pathways, are still very limited. Here, by employing both in vivo and in vitro models, we report that METTL14 was indispensable for post-implantation embryonic development by facilitating the conversion from naive to primed state of the epiblast. Depletion of Mettl14 lead to conspicuous embryonic growth retardation from E6.5 mainly as a result of resistance to differentiation, which further lead to embryonic lethality early in gestation. Our data highlight the critical function of METTL14, as an m6A modification regulator, in orchestrating early mouse embryogenesis.

developmental biology↗