Biology subjects

Xu, Y.-W.

Publications and source records attributed to Xu, Y.-W..

7 recordsLinked to original sources

bioRxiv2026

Postsynaptic TAK1-GluN2B axis supports hippocampal synaptic integrity and cognitive function during aging

Transforming growth factor {beta}-activated kinase 1 (TAK1) is a serine/threonine kinase best known for its roles in immune and stress-response signaling, yet its physiological function in mature neurons remains poorly understood. Here we identify neuronal TAK1 as a regulator of excitatory synaptic integrity, hippocampal plasticity and memory. Conditional reduction of TAK1 in forebrain excitatory neurons impaired short- and long-term memory and was accompanied by attenuated long-term potentiation in the hippocampus. At the cellular level, TAK1 deficiency reduced dendritic spine density and suppressed excitatory synaptic transmission, whereas genetic or pharmacological disruption of TAK1 kinase activity recapitulated these synaptic deficits. Mechanistically, TAK1 localized to the postsynaptic compartment of excitatory synapses and associated with PSD-95. Phosphoproteomic analysis of isolated postsynaptic density fractions revealed coordinated changes in synaptic phosphorylation following TAK1 reduction, including decreased phosphorylation of the NMDA receptor subunit GluN2B at serine 920. Analyses of phosphodeficient and phosphomimetic GluN2B mutants supported a role for S920 phosphorylation downstream of TAK1 in maintaining dendritic spine density, excitatory synaptic transmission and spontaneous synaptic calcium activity. Notably, synaptic TAK1 level was reduced in the aged hippocampus. Re-expressing neuronal TAK1 in aged mice increased dendritic spine density, enhanced hippocampal synaptic plasticity, and improved memory performance. Together, these findings define a postsynaptic TAK1-GluN2B signaling axis that supports excitatory synaptic function and suggest that reduced synaptic TAK1 signaling may contribute to hippocampal vulnerability during aging.

neuroscience↗

bioRxiv2025

Superficial stromal cell population in the mouse uterus require METTL14 for development and functional competence to support embryo implantation

Uterine stromal cells are critical for pregnancy, coordinating embryo implantation, placental development, and maintenance of gestation. Single-cell RNA-seq analyses have identified two distinct stromal cell populations in the mouse uterus: superficial and deep stromal cells. However, their functional specialization remains unresolved. Here, we show that mice lacking methyltransferase-like 14 (METTL14), a core enzyme of the m6A methyltransferase complex, exhibit a selective depletion of superficial stromal cells while preserving deep stromal cells. This genetic model allowed us to investigate the physiological role of superficial stromal cells in uterine function. Paralleled by the aberrant development and loss of superficial stromal cells, Mettl14 deletion impaired embryo implantation and decidualization. Transcriptomic profiling revealed that Mettl14 deficiency disrupts hormonal signaling by upregulating estrogen (E2)-responsive genes and downregulating progesterone (P4)-responsive genes, resulting in aberrant development and loss of superficial stromal cells. Mechanistically, Mettl14 ablation reduces m6A methylation in the 3'-UTR of Esr1 mRNA, thereby impairing m6A-dependent mRNA degradation and elevating ESR1 expression, which amplifies E2 signaling. This study underscores the essential role of METTL14 in maintaining the superficial stromal cell population required for embryo implantation by regulating Esr1 mRNA stability through m6A modification.

physiology↗

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↗

bioRxiv2022

Endothelial TET2 Regulates Cardiac Remodeling by Modifying Endothelial-to-Mesenchymal Transition

DNA methylation modification has been proved to play an important role in heart diseases. In this study, the role of Ten-Eleven Translocation-2 (TET2), which is a key demethylation enzyme, is investigated in cardiac remodeling. TET2 is abundant in endothelial cells but decreased in hypertrophic hearts. TET2 knockdown in endothelial cells triggers endothelial-to-mesenchymal transition (EndMT), while overexpression of TET2 inhibits the EndMT. In vivo, Cdh5-CreERT2/TET2flox/flox; Rosa26-mTmG+/- mice are developed and undergo transverse aortic constriction (TAC) subsequently to induce pathological cardiac hypertrophy model. Hearts of Cdh5-CreERT2/TET2flox/flox mice show more severe hypertrophy and fibrosis than controls in the TAC model. Furthermore, EGLN3 is identified to participate in EndMT as the downstream target of TET2 by using RNA sequencing and whole-genome bisulfite sequencing (WGBS). Finally, vitamin C, which can mimic TET2 restoration, is found to partially improve cardiac function and inhibit myocardial fibrosis. These insights into how TET2 alleviates cardiac fibrosis may open new avenues for treating cardiac remodeling in the future.

genetics↗

bioRxiv2022

LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression

Lysyl-oxidase like-2 (LOXL2) regulates extracellular matrix remodeling and promotes tumor invasion and metastasis. Altered metabolism is a core hallmark of cancer, however, it remains unclear whether and how LOXL2 contributes to tumor metabolism. Here, we found that LOXL2 and its catalytically inactive L2{Delta}13 splice variant also function as novel deacetylases that trigger metabolic reprogramming during malignant transformation. Integrated transcriptomic and metabolomic analysis revealed that L2{Delta}13-overexpressing transgenic mice displayed perturbed glucose and lipid metabolism, which was associated with increased hepatic fibrosis and enhanced formation of precancerous lesions induced by chemical carcinogens, such as carbon tetrachloride and N-nitrosomethylbenzylamine. Furthermore, both LOXL2 and L2{Delta}13 boosted glucose metabolism of esophageal tumor cells, thereby facilitating tumor cell proliferation in vitro and in vivo. Mechanistically, LOXL2 and L2{Delta}13 interacted physically with several glycolic proteins including aldolase A to enhance their enzymatic activities and mobilization from the actin cytoskeleton. Using SILAC followed by proteomic analysis, we identified LOXL2 as a deacetylase targeting metabolic proteins in esophageal cancer. Importantly, both LOXL2 and L2{Delta}13 directly catalyzed the deacetylation of aldolase A at K13, resulting in enhanced glycolysis which subsequently reprogramed tumor metabolism and promoted tumor progression. High level expression of LOXL2/L2{Delta}13 combined with decreased acetylation of aldolase-K13 predicted poor clinical outcome in patients with esophageal cancer. In summary, we have characterized a novel molecular mechanism that mediates the pro-tumorigenic activity of LOXL2 independently of its classical amine oxidase activity. These findings may enable the future development of therapeutic agents targeting the metabolic machinery via LOXL2 or L2{Delta}13.

cell biology↗