Qingran Kong

Metabolism is a major regulator of pre-implantation embryonic development, but pre-implantation development arrest (PIDA) due to abnormal metabolisms remains ambiguous. By estimating a weight for each metabolic reaction using the translatome data, we developed a computational tool to perform pre-implantation embryos metabolic analysis (PEMA), and uncovered that the embryos exist in high activities of lactate dehydrogenase and lactate synthesis when major zygotic genome activation (ZGA) occurs in humans and mice. The insufficiency of endogenous lactate was predicted by PEMA in human 8-cell PIDA and corrected human tripronuclear (ch3PN) embryos, which was coordinated with failed H3K18lac and major ZGA. In transcriptomes, the human PIDA embryos resembled endogenous lactate-deprived mouse embryos. Lac-CoA addition could promote H3K18lac, major ZGA, and ch3PN pre-implantation development. Collectively, our study decodes the metabolic abnormalities in human PIDA embryos. The experimental validation suggests that PEMA offers an opportunity to study metabolic heterogeneity in early embryos.

Background: FGFRs genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in cancers, leading to the initiation and progression of tumors by enhancing FGFR signaling. The substantial problems arising from the lack of decisive clinical evidence have resulted in the cessation of some inhibitor applications, and identifying effective small molecule inhibitors that selectively target FGFRs can advance the therapy of cancers driven by FGFRs abnormalities. Methods: The three-dimensional structure of the FGFR1/2/3/4 protein and the amino acid positions within the tyrosine kinase domain were downloaded from the PDB database, and small molecule data were extracted from the ZINC15 database. Then, we used molecular docking and dynamics simulations to assess compounds interacting with FGFR proteins, and screening potential small molecules targeting FGFR. Finally, we evaluated its effects by two CRC cell line HCT116 and NCI-H716. Results: In the study, by docking with 2.8 million small molecules, we identified three promising FGFR small molecule inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of the three compounds, we found that ZINC000101867325 could form the stable binding interactions with FGFR1/2/3. And, ZINC000101867325 inhibited the activity of FGFR signaling, and resulted in cell apoptosis and decrease in cell proliferation and migration in colorectal cancer cell lines. In addition, ZINC000101867325 is also predicted to target FGFR2 mutations in colorectal cancer patients. Conclusion: We predicted three small molecules targeting FGFRs, and ZINC000101867325 shows superior chemical bond types and stability with FGFR1/2/3, and inhibits FGFR signaling in CRC cell lines. This study provides novel FGFRs inhibitors, which enrich treatment strategies for cancers.

Microplastics (MPs) are considered one of the main causes of male and female infertility. However, the reproductive toxicity and its related mechanisms are currently understood primarily through animal models with acute exposure to MPs. In this study, we demonstrate that low-dose exposure to polystyrene microplastics (PSMPs) leads to severely abnormal reproduction in females, manifested by oocyte meiotic maturation defect. Mechanistically, PSMPs exposure induce the overactivation of cell metabolism pathways, insufficient HDACs, and H4K16 hyperacetylation in oocytes both in vivo and in vitro. When an HDAC3 inhibitor is added, the oocyte maturation defect, overactivation of cell metabolism pathways, and H4K16 hyperacetylation are recapitulated. Conversely, the overexpression of HDAC3 can rescue the defects in meiotic maturation induced by PSMPs. Our observations suggest a direct link between the maturation defects caused by PSMPs and HDAC3 insufficiency. Thus, we propose potential treatments to address the meiotic maturation defect of oocytes in women highly exposed to MPs by activating or supplying HDAC3.

Long noncoding RNAs (lncRNAs) are increasingly being recognized as modulators of mammalian early embryonic development. However, in pig, it is seldom investigated. In this study, lncRNAs were predicted using single-cell RNA-seq data on porcine early embryos from oocyte to early blastocyst. We further identified a novel nuclear long intergenic noncoding RNA (lincRNA),linc-321, which was specifically and highly expressed in 1-cell embryo, and it was indispensable for the formation of zygote and early embryonic development in pig. Its knockdown by locked nucleic acid (LNA)-siRNA could result in developmental arrest at 1-cell stage with failure of pronuclear envelope fusion (PEF). Mechanistically, linc-321 facilitates the recruitment of SUZ12 to the TSS region of MYT1. And this recruitment is instrumental in establishing H3K27me3 modifications, consequently leading to the repression of MYT1 expression. Moreover, the failure of PEF and developmental arrest induced by loss oflinc-321could be rescued by addition oflinc-321with LNA-siRNA targeting site deletion andMYT1knockdown. Thus, as functional lincRNA characterized in pig,linc-321provides the clues for investigating the strictly regulated process of early embryonic development.

Background Zygotic genome activation (ZGA) is an important event in the early embryo development, and human embryo developmental arrest has been highly correlated with ZGA failure in clinical studies. Although a few studies have linked maternal factors to mammalian ZGA, more studies are needed to fully elucidate the maternal factors that are involved in ZGA. Methods and results In this study, we utilized published single-cell RNA sequencing data from a Dux-mediated mouse embryonic stem cell to induce a 2-cell-like transition state and selected potential drivers for the transition according to an RNA velocity analysis. Conclusions An overlap of potential candidate markers of 2-cell-like-cells identified in this research with markers generated by various data sets suggests that Trim75 is a potential driver of minor ZGA and may recruit EP300 and establish H3K27ac in the gene body of minor ZGA genes, thereby contributing to mammalian preimplantation embryo development.

The dynamic changes in lipids during early embryonic development in mammals have not yet been comprehensively investigated. In a recent paper published in Nature Cell Biology, Jin Zhang et al. reported the dynamic lipid landscapes during preimplantation embryonic development in mice and humans. They highlight the crucial role of lipid unsaturation in regulating embryogenesis.

Copy number variations (CNVs) play a vital role in regulating genes expression and tumorigenesis. We explored the copy number alterations in early-stage lung adenocarcinoma using high-throughput sequencing and nucleic acid flight mass spectrometry technology, and found that 8q22.1-22.2 is frequently amplified in lung adenocarcinoma tissues. COX6C localizes on the region and its expression is notably enhanced that driven by amplification in lung adenocarcinoma. Knockdown of COX6C significantly inhibits the cell proliferation, and induces S-G2/M cell cycle arrest, mitosis deficiency and apoptosis. Moreover, COX6C depletion causes a deficiency in mitochondrial fusion, and impairment of oxidative phosphorylation. Mechanistically, COX6C-induced mitochondrial deficiency stimulates ROS accumulation and activates AMPK pathway, then leading to abnormality in spindle formation and chromosome segregation, activating spindle assemble checkpoint, causing mitotic arrest, and ultimately inducing cell apoptosis. Collectively, we suggested that copy amplification-mediated COX6C upregulation might serves as a prospective biomarker for prognosis and targeting therapy in patients with lung adenocarcinoma.

Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation (ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, which could be rescued by the addition of Lac-CoA and recapitulated by overexpression of H3K18R mutation. By profiling the landscape of H3K18lac during mouse preimplantation development, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and correlates with their expressions. In humans, H3K18lac is also enriched in ZGA markers and temporally concomitant with their expressions. Taken together, we profile the landscapes of H3K18lac in mouse and human preimplantation embryos, and demonstrate the important role for H3K18lac in major ZGA, showing that a conserved metabolic mechanism underlies preimplantation development of mammalian embryos.