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Abstract Female fecundity declines in a nonlinear manner with age during the reproductive years, even as ovulatory cycles continue, which reduces female fertility, disrupts metabolic homeostasis, and eventually induces various chronic diseases. Despite this, the aging‐related cellular and molecular changes in human ovaries that occur during these reproductive years have not been elucidated. Here, single‐cell RNA sequencing (scRNA‐seq) of human ovaries is performed from different childbearing ages and reveals that the activation of the pyroptosis pathway increased with age, mainly in macrophages. The enrichment of pyroptotic macrophages leads to a switch from a tissue‐resident macrophage (TRM)‐involve immunoregulatory microenvironment in young ovaries to a pyroptotic monocyte‐derived macrophage (MDM)‐involved proinflammatory microenvironment in middle‐aged ovaries. This remolded ovarian immuno‐microenvironment further promotes stromal cell senescence and accelerated reproductive decline. This hypothesis is validated in a series of cell and animal experiments using GSDMD‐KO mice. In conclusion, the work expands the current understanding of the ovarian aging process by illustrating a pyroptotic macrophage‐involved immune mechanism, which has important implications for the development of novel strategies to delay senescence and promote reproductive health.

Introduction: Investigating the genetic footprints of historical temperature selection can get insights to the local adaptation and feasible influences of climate change on long-term population dynamics. Object: Chicken is a significative species to study genetic adaptation on account of its similar domestication track related to human activity with the most diversified varieties. Yet, few studies have demonstrated the genetic signatures of its adaptation to naturally tropical and frigid environments. Method: Here, we generated whole genome resequencing of 119 domesticated chickens in China including the following breeds which are in order of breeding environmental temperature from more tropical to more frigid: Wenchang chicken (WCC), green-shell chicken (GSC), Tibetan chicken (TBC), and Lindian chicken (LDC). Results: Our results showed WCC branched off earlier than LDC with an evident genetic admixture between WCC and LDC, suggesting their closer genetic relationship. Further comparative genomic analyses solute carrier family 33 member 1 (SLC33A1) and thyroid stimulating hormone receptor (TSHR) genes exhibited stronger signatures for positive selection in the genome of the more tropical WCC. Furthermore, genotype data from about 3,000 African local ecotypes confirmed that allele frequencies of single nucleotide polymorphisms (SNPs) in these 2 genes appeared strongly associated with tropical environment adaptation. In addition, the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) gene exhibited a strong signature for positive selection in the LDC genome, and SNPs with marked allele frequency differences indicated a significant relationship with frigid environment adaptation. Conclusion: Our findings partially clarify how selection footprints from environmental temperature stress can lead to advantageous genomic adaptions to tropical and frigid environments in poultry and provide a valuable resource for selective breeding of chickens.

Abstract Abnormal resumption of meiosis and decreased oocyte quality are hallmarks of maternal aging. Transcriptional silencing makes translational control an urgent task during meiosis resumption in maternal aging. However, insights into aging‐related translational characteristics and underlying mechanisms are limited. Here, using multi‐omics analysis of oocytes, it is found that translatomics during aging is related to changes in the proteome and reveals decreased translational efficiency with aging phenotypes in mouse oocytes. Translational efficiency decrease is associated with the N6‐methyladenosine (m6A) modification of transcripts. It is further clarified that m6A reader YTHDF3 is significantly decreased in aged oocytes, inhibiting oocyte meiotic maturation. YTHDF3 intervention perturbs the translatome of oocytes and suppress the translational efficiency of aging‐associated maternal factors, such as Hells, to affect the oocyte maturation. Moreover, the translational landscape is profiled in human oocyte aging, and the similar translational changes of epigenetic modifications regulators between human and mice oocyte aging are observed. In particular, due to the translational silence of YTHDF3 in human oocytes, translation activity is not associated with m6A modification, but alternative splicing factor SRSF6. Together, the findings profile the specific translational landscapes during oocyte aging in mice and humans, and uncover non‐conservative regulators on translation control in meiosis resumption and maternal aging.

Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement by explaining the genome of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of the UGT family 2 subfamily B of UGT genes. The first chromosome-level assembly and genetic characterization of the tolerance to a highly toxic diet suggest that the sika deer genome may serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

Abstract Background Although the extreme environmental adaptation of organisms is a hot topic in evolutionary biology, genetic adaptation to high-altitude environment remains poorly characterized in ectothermic animals. Squamates are among the most diverse terrestrial vertebrates, with tremendous ecological plasticity and karyotype diversity, and are a unique model system to investigate the genetic footprints of adaptation. Results We report the first chromosome-level assembly of the Mongolian racerunner (Eremias argus) and our comparative genomics analyses found that multiple chromosome fissions/fusions events are unique to lizards. We further sequenced the genomes of 61 Mongolian racerunner individuals that were collected from altitudes ranging from ~ 80 to ~ 2600 m above sea level (m.a.s.l.). Population genomic analyses revealed many novel genomic regions under strong selective sweeps in populations endemic to high altitudes. Genes embedded in those genomic regions are mainly associated with energy metabolism and DNA damage repair pathways. Moreover, we identified and validated two substitutions of PHF14 that may enhance the lizards’ tolerance to hypoxia at high altitudes. Conclusions Our study reveals the molecular mechanism of high-altitude adaptation in ectothermic animal using lizard as a research subject and provides a high-quality lizard genomic resource for future research.

In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase(OGA) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA, we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein–coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a, Gm7788, Gm41780, Trpc7, Gm29036, and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation.

N4-acetylcytidine (ac4C), a newly identified epigenetic modification within mRNA, has been characterized as a crucial regulator of mRNA stability and translation efficiency. However, the role of ac4C during oocyte maturation, the process mainly controlled via post-transcriptional mechanisms, has not been explored. N-acetyltransferase 10 (NAT10) is the only known enzyme responsible for ac4C production in mammals and ac4C-binding proteins have not been reported yet. In this study, we have documented decreasing trends of both ac4C and NAT10 expression from immature to mature mouse oocytes. With NAT10 knockdown mediated by small interfering RNA (siRNA) in germinal vesicle (GV)-stage oocytes, ac4C modification was reduced and meiotic maturation in vitro was significantly retarded. Specifically, the rate of first polar body extrusion was significantly decreased with NAT10 knockdown (34.6%) compared to control oocytes without transfection (74.6%) and oocytes transfected with negative control siRNA (72.6%) (p < 0.001), while rates of germinal vesicle breakdown (GVBD) were not significantly different (p = 0.6531). RNA immunoprecipitation and high-throughput sequencing using HEK293T cells revealed that the modulated genes were enriched in biological processes associated with nucleosome assembly, chromatin silencing, chromatin modification and cytoskeletal anchoring. In addition, we identified TBL3 as a potential ac4C-binding protein by a bioinformatics algorithm and RNA pulldown with HEK293T cells, which may mediate downstream cellular activities. Taken together, our results suggest that NAT10-mediated ac4C modification is an important regulatory factor during oocyte maturation in vitro and TBL3 is a potential ac4C-binding protein.

Dietary fiber intake is associated with a low incidence of suffering from metabolic syndrome. To explore the potential health benefits of walnut meal dietary fiber (WMDF) as a prebiotic, the functional role of WMDF on metabolic syndrome in mice induced by high fructose diet (20%, HF) was investigated. The animal experiment results showed that administration of WMDF to HF-fed mice alleviated abnormal body weight gain, insulin resistance, oxidative stress, lipid metabolism disorders and inflammation. Histopathological observation confirmed the preventative effects of WMDF on hepatic steatosis and vascular endothelial dysfunction. Also, WMDF intake increased the production of acetic acid, propionic acid and butyric acid. Moreover, WMDF ingestion effectively improved the disorder of gut microbiota caused by HF, increased the diversity of gut microbiota and the relative abundance of short-chain fatty acids-producing bacteria. These findings demonstrate WMDF can be used as a prebiotic to prevent HF-induced metabolic syndrome.

The acute thermal response has been extensively studied in commercial chickens because of the adverse effects of heat stress on poultry production worldwide. Here, we performed whole-genome resequencing of autochthonous Niya chicken breed native to the Taklimakan Desert region as well as of 11 native chicken breeds that are widely distributed and reared under native humid and temperate areas. We used combined statistical analysis to search for putative genes that might be related to the adaptation of hot arid and harsh environment in Niya chickens. We obtained a list of intersected candidate genes with log2 θπ ratio, FST and XP-CLR (including 123 regions of 21 chromosomes with the average length of 54.4 kb) involved in different molecular processes and pathways implied complex genetic mechanisms of adaptation of native chickens to hot arid and harsh environments. We identified several selective regions containing genes that were associated with the circulatory system and blood vessel development (BVES, SMYD1, IL18, PDGFRA, NRP1, and CORIN), related to central nervous system development (SIM2 and NALCN), related to apoptosis (CLPTM1L, APP, CRADD, and PARK2) responded to stimuli (AHR, ESRRG FAS, and UBE4B) and involved in fatty acid metabolism (FABP1). Our findings provided the genomic evidence of the complex genetic mechanisms of adaptation to hot arid and harsh environments in chickens. These results may improve our understanding of thermal, drought, and harsh environment acclimation in chickens and may serve as a valuable resource for developing new biotechnological tools to breed stress-tolerant chicken lines and or breeds in the future.

Summary: Decades of artificial selection have significantly improved performance and efficiency of animal production systems. However, little is known about the microevolution of genomes due to intensive breeding. Using whole-genome sequencing, we document dynamic changes of chicken genomes under divergent selection on adiposity over 19 generations. Directional selection reduced within-line but increased between-line genomic differences. We observed that artificial selection tended to result in recruitment of preexisting variations of genes related to adipose tissue growth. In addition, novel mutations contributed to divergence of phenotypes under selection but contributed significantly less than preexisting genomic variants. Integration of 15 generations genome sequencing, genome-wide association study, and multi-omics data further identified that genes involved in signaling pathways important to adipogenesis, such as autophagy and lysosome (URI1, MBL2), neural system (CHAT), and endocrine (PCSK1) pathways, were under strong selection. Our study provides insights into the microevolutionary dynamics of domestic animal genomes under artificial selection.

Dioscin is a natural steroidal saponin that can be isolated from Chinese medicine, such as Dioscoreae rhizoma. It has wild range of pharmacological activities such as hepatoprotection, a lipid-lowering effect, and anti-inflammation. Recently, mounting studies reported the anticancer effect of dioscin on a variety of tumor cells. However, the potential effect of dioscin on the epithelial-mesenchymal transition (EMT) of HepG2 cells is unclear. In the present study, dioscin was identified to inhibit transforming growth factor-β1 (TGF-β1) and induced invasive and migratory behavior of HepG2 cells. Consistently, the expression of the epithelial marker E-cadherin and gap junction proteins increased following dioscin treatment, while mesenchymal markers decreased, including N-cadherin, Vimentin, Snail, and Slug. Furthermore, we discovered that TGF-β1 induces phosphorylation of JNK, p38, and Erk, whereas the activation of these kinases was reversed by dioscin treatment in a dose-dependent manner. With the addition of Asiatic acid, a p38 activator, the inhibitory effect of dioscin on EMT was reversed. Taken together, these data indicated that dioscin inhibits EMT in HepG2 cells, which is mediated in large part by inhibition of the p38-MAPK signaling.