Biology subjects

Yang, X.-Q.

Publications and source records attributed to Yang, X.-Q..

5 recordsLinked to original sources

bioRxiv2025

Programmed downregulation of METTL3 is essential for decidualization in both humans and mice

N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an essential role in regulating gene expression. Our prior research, alongside that of others, demonstrated that conditional uterine knockout of methyltransferase-like 3 (METTL3), the enzyme responsible for m6A modification, led to complete failure of embryo implantation and decidualization. Intriguingly, METTL3 expression is downregulated rather than upregulated in human endometrial stromal cells (HESCs) during in vitro decidualization and in mouse decidual tissues during pregnancy. We hypothesized that this decline in METTL3 expression is indispensable for successful decidualization. To test this hypothesis, we overexpressed METTL3 in HESCs and observed impaired decidualization in vitro. Additionally, we generated genetically engineered mice with uterine-specific METTL3 overexpression using Pgr-Cre, which exhibited subfertility mainly due to impaired decidualization. Further investigation revealed a marked decrease in HAND2, a well-established regulator of decidualization, following METTL3 overexpression. Mechanistically, we uncovered that METTL3 destabilizes HAND2 mRNA via m6A modification at the 5'-UTR. In summary, our study underscores the critical role of programmed METTL3 downregulation in decidualization by sustaining HAND2 expression.

physiology↗

bioRxiv2025

CTCF is crucial for decidualization of uterine stromal cells through facilitating HOXA11 expression

CCCTC-binding factor (CTCF), a highly versatile transcriptional regulator and chromatin architectural protein, plays a pivotal role in mammalian development. In this study, we investigated the function of CTCF in uterine biology during pregnancy. We observed that CTCF expression in the human endometrium decreases from the proliferative to the secretory phase of the menstrual cycle. Similarly, in cultured human endometrial stromal cells (hESCs), CTCF expression declines during in vitro decidualization. Using siRNA-mediated knockdown, we demonstrated that CTCF is essential for the early phase of decidualization but dispensable in later stages. Notably, CTCF depletion reduces the expression of HOXA11, a well-established regulator of decidualization, and overexpression of HOXA11 rescues the decidualization defects caused by CTCF loss, identifying HOXA11 as a key downstream effector of CTCF. Mechanistically, CTCF binds to the HOXA11 promoter to facilitate its transcriptional activation. Furthermore, uterine-specific knockout of CTCF in Pgr-Cre mice leads to female infertility, characterized by diminished HOXA11 expression, impaired uterine receptivity, and defective decidualization. Collectively, our findings highlight the critical role of the CTCF-HOXA11 axis in decidualization in both humans and mice, providing novel insights into the molecular regulation of this process and potential therapeutic targets for reproductive disorders.

physiology↗

bioRxiv2025

NAT10 governs uterine function and fertility by stabilizing progesterone receptor mRNA via ac4C modification

The N4-acetylcytidine (ac4C) modification is one of the most abundant chemical modifications in mammalian transcriptome, which plays a crucial role in regulating gene expression across various biological processes. In this study, we investigate the role of N4-acetyltransferase 10 (NAT10), the sole enzyme responsible for catalyzing the ac4C modification, in uterine function. Our findings revealed that knockdown of NAT10 in cultured human endometrial stromal cells leads to decreased progesterone receptor (PGR) expression and compromised decidualization. Mechanistically, NAT10 is found to enhance the stability of PGR mRNA through its ac4C modification in the coding sequence (CDS). Furthermore, conditional deletion of Nat10 in the mouse uterus using Pgr-Cre resulted in defective pubertal uterine development, characterized by a thinner stroma and reduced endometrial gland number. These mice were infertile in adulthood, experiencing failures in both implantation and decidualization. However, heterozygous Nat10 conditional knockout mice showed reduced NAT10 expression in the uterus without affecting uterine development or fertility. To bridge the gap between heterozygous and homozygous knockout conditions, we employed Remodelin, an inhibitor of NAT10, in adult female mice, to mimic an intermediate gene dosage. Our results demonstrated that inhibiting NAT10 with Remodelin preserved uterine structures but disrupted the PGR signaling pathway, leading to impaired uterine function during pregnancy. In conclusion, our study provides compelling evidence that NAT10 safeguards uterine function and fertility by regulating the ac4C modification of PGR mRNA. SignificanceHere we identified NAT10-catalyzed ac4C modification of progesterone receptor (PGR) mRNA as a crucial mechanism regulating PGR expression by enhancing its mRNA stability. In vitro studies using human endometrial stromal cells show that the NAT10-PGR axis is required for decidualization. Additionally, genetic and pharmacologic manipulations in mice further demonstrate the necessity of NAT10-dependent P4/PGR signaling for uterine function during implantation and decidualization. Our findings highlight the importance of NAT10-mediated ac4C modification in maintaining PGR expression and uterine function.

physiology↗

bioRxiv2025

X-ray irradiation hinders flight ability of Cydia pomonella male moths by energy metabolism dysfunction

Flight in insects is essential for behaviors such as courtship, foraging, and migration, with energy metabolism serving as its primary energy source. Previous study indicates that X-ray irradiation, even at optimized doses, compromises the flight capacity of male Cydia pomonella moths utilized in sterile insect technique (SIT) programs. However, the underlying mechanisms of this phenomenon have not been fully understood. In this study, we report that the disruption of energy metabolism processes contributing to the diminished flight capabilities observed in X-ray irradiated sterile C. pomonella moths. Compared to the non-irradiated group, irradiated moths exhibited significantly decreased adenosine triphosphate (ATP) levels. Furthermore, a reduction in the enzymatic activity of key components within carbon metabolism pathways was observed, including citrate synthase (CS) in the tricarboxylic acid cycle (TCA), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), glycerol 3-phosphate dehydrogenase (GPDH) in glycolysis, and 3-Hydroxyl-CoA dehydrogenase (HOAD) in fatty acid metabolism. Transcriptional analysis revealed downregulation of expression of genes associated with energy metabolism in the primary locomotor tissues post-irradiation, specifically those encoding CS (CS2), GAPDH (Gapdh2), GPDH (GPD2), and HOAD (HADHA, HADH1, B0272, HADH2) enzymes. Additionally, exogenous supplementation with decanoic acid and citric acid, the agonist and product of CS respectively, enhanced the TCA cycle, increased energy production, and restored flight capacity in sterile moths. These findings not only confirm that X-ray irradiation disrupts energy metabolism leading to impaired flight, but also offer a potential strategy to overcome this limitation before releasing sterile moths as component of integrated pest management programme using the SIT. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/644052v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@c05e61org.highwire.dtl.DTLVardef@17461d9org.highwire.dtl.DTLVardef@1c41b70org.highwire.dtl.DTLVardef@1e58b48_HPS_FORMAT_FIGEXP M_FIG Graphic Abstract C_FIG

zoology↗

bioRxiv2022

Sublethal and transgenerational effects of lambda-cyhalothrin and abamectin on the development and reproduction of Cydia pomonella

The codling moth Cydia pomonella (Lepidoptera: Tortricidae) is a major invasive pest of pome fruits and walnuts worldwide. Lambda-cyhalothrin (LCT) and abamectin (AM) have been frequently used in C. pomonella control, but control of this pest is very difficult because shortly after hatching, larvae of this insect bore tunnels and hide inside host plant fruit. In this study, a simulated field spray bioassay method was developed against neonate larvae of C. pomonella and concentration-response bioassays were conducted to evaluate the susceptibility of the neonate larvae to LCT and AM. Exposure of neonate larvae to sublethal concentrations (LC30) of LCT or AM significantly reduced the survival rate of larvae (4th and 5th instars), lowered the mean weight of larvae and pupae, and decreased the daily maximal number of eggs laid and the total number of eggs laid (fecundity) per female. The sublethal effects, including reduced body mass, mean fecundity and net reproductive rate, extended mean generation time, and shortened oviposition period, were also found in transgenerational offspring. Furthermore, the transgenerational maternal effects were more obvious for AM than LCT, in comparison to the control. Additionally, the estimated population size was decreased by exposure to LC30 of LCT and AM, and the observed reduction of fecundity and population size within and across generations was likely the result of the downregulation of the reproduction-related vitellogenin gene (CpVg) after exposure to LC30 of LCT and AM. These results provide a better understanding of the overall effects of LCT and AM on C. pomonella and the transgenerational effects which should be taken into consideration when using insecticides in order to control C. pomonella.

pharmacology and toxicology↗