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Signal Transduction and Targeted Therapy Sep 2023Intraluminal lymphatic valves (LVs) and lymphovenous valves (LVVs) are critical to ensure the unidirectional flow of lymphatic fluid. Morphological abnormalities in...
Intraluminal lymphatic valves (LVs) and lymphovenous valves (LVVs) are critical to ensure the unidirectional flow of lymphatic fluid. Morphological abnormalities in these valves always cause lymph or blood reflux, and result in lymphedema. However, the underlying molecular mechanism of valve development remains poorly understood. We here report the implication of Efnb2-Ephb4-Rasa1 regulated Erk signaling axis in lymphatic valve development with identification of two new valve structures. Dynamic monitoring of phospho-Erk activity indicated that Erk signaling is spatiotemporally inhibited in some lymphatic endothelial cells (LECs) during the valve cell specification. Inhibition of Erk signaling via simultaneous depletion of zygotic erk1 and erk2 or treatment with MEK inhibitor selumetinib causes lymphatic vessel hypoplasia and lymphatic valve hyperplasia, suggesting opposite roles of Erk signaling during these two processes. ephb4b mutants, efnb2a;efnb2b or rasa1a;rasa1b double mutants all have defective LVs and LVVs and exhibit blood reflux into lymphatic vessels with an edema phenotype. Importantly, the valve defects in ephb4b or rasa1a;rasa1b mutants are mitigated with high-level gata2 expression in the presence of MEK inhibitors. Therefore, Efnb2-Ephb4 signaling acts to suppress Erk activation in valve-forming cells to promote valve specification upstream of Rasa1. Not only do our findings reveal a molecular mechanism of lymphatic valve formation, but also provide a basis for the treatment of lymphatic disorders.
Topics: Endothelial Cells; Lymphatic Vessels; Signal Transduction; Phosphorylation; Mitogen-Activated Protein Kinase Kinases
PubMed: 37691058
DOI: 10.1038/s41392-023-01571-9 -
Zygote (Cambridge, England) Oct 2023Based on the fact that the follicular phase in the menstrual cycle has length variation, it has been assumed that the duration of oestrogen (E2) administration could... (Randomized Controlled Trial)
Randomized Controlled Trial
Based on the fact that the follicular phase in the menstrual cycle has length variation, it has been assumed that the duration of oestrogen (E2) administration could also be variable; therefore, for the first time, this randomized clinical trial study was conducted to investigate and compare the duration of estradiol administration and the effect on pregnancy outcomes in the cleavage-stage frozen embryo transfer (FET) cycle. We included women aged 20-40 with a normal uterus on hysteroscopy between September and December 2022 and who were divided randomly into three groups: group A [ = 79; 8-11 days of oestrogen before progesterone (P4) supplementation], group B ( = 78; 12-14 days of oestrogen before P4 supplementation), and group C ( = 76; 15-18 days of estrogen before P4 supplementation). Serum levels for E2 on the initial progesterone day and P4 on the transfer day were measured. The effect of the duration of E2 administration on clinical pregnancy and pregnancy loss was investigated. We found no significant differences between the three groups in the clinical pregnancy rate ( = 0.696) and clinical abortion rate ( = 0.925) according to the duration of the E2. There was no significant difference in the E2, P4 levels, and endometrial thickness in pregnant vs. non-pregnant women. The mean of the E2 and P4 levels was 300.03 ± 22.21 and 25.36 ± 5.78, respectively. Our findings suggest that variation in the length of E2 administration (8-18 days) before progesterone initiation in day 3 FET cycles does not affect pregnancy outcome and transfer time can be flexibly arranged.
Topics: Pregnancy; Female; Humans; Pregnancy Outcome; Estradiol; Progesterone; Embryo Transfer; Pregnancy Rate; Estrogens; Retrospective Studies
PubMed: 37448263
DOI: 10.1017/S096719942300031X -
International Journal of Molecular... Jul 2023The changes in epigenetic modifications during early embryonic development significantly impact mammalian embryonic genome activation (EGA) and are species-conserved to...
The changes in epigenetic modifications during early embryonic development significantly impact mammalian embryonic genome activation (EGA) and are species-conserved to some degree. Here, we reanalyzed the published RNA-Seq of human, mouse, and goat early embryos and found that (zinc finger protein 296) expression was higher at the EGA stage than at the oocyte stage in all three species (adjusted -value < 0.05 |log2(foldchange)| ≥ 1). Subsequently, we found that was conserved across human, mouse, goat, sheep, pig, and bovine embryos. In addition, we identified that ZFP296 interacts with the epigenetic regulators KDM5B, SMARCA4, DNMT1, DNMT3B, HP1β, and UHRF1. The Cys-His(C2H2) zinc finger domain TYPE2 TYPE3 domains of ZFP296 co-regulated the modification level of the trimethylation of lysine 9 on the histone H3 protein subunit (H3K9me3). According to ChIP-seq analysis, ZFP296 was also enriched in , , , , and in the mESC genome. Then, knockdown of the expression of at the late zygote of the mouse led to the early developmental arrest of the mouse embryos and failure resulting from a decrease in H3K9me3. Together, our results reveal that is an H3K9me3 modulator which is essential to the embryonic genome activation of mouse embryos.
Topics: Animals; Cattle; Humans; Mice; CCAAT-Enhancer-Binding Proteins; DNA Helicases; Embryonic Development; Histones; Mouse Embryonic Stem Cells; Nuclear Proteins; Sheep; Swine; Transcription Factors; Ubiquitin-Protein Ligases; Zygote; Embryo, Mammalian
PubMed: 37511136
DOI: 10.3390/ijms241411377 -
Trends in Biochemical Sciences Aug 2023Spatiotemporal regulation of cell type-specific gene expression is essential to convert a zygote into a complex organism that contains hundreds of distinct cell types. A... (Review)
Review
Spatiotemporal regulation of cell type-specific gene expression is essential to convert a zygote into a complex organism that contains hundreds of distinct cell types. A class of cis-regulatory elements called enhancers, which have the potential to enhance target gene transcription, are crucial for precise gene expression programs during development. Following decades of research, many enhancers have been discovered and how enhancers become activated has been extensively studied. However, the mechanisms underlying enhancer silencing are less well understood. We review current understanding of enhancer decommissioning and dememorization, both of which enable enhancer silencing. We highlight recent progress from genome-wide perspectives that have revealed the life cycle of enhancers and how its dynamic regulation underlies cell fate transition, development, cell regeneration, and epigenetic reprogramming.
Topics: Animals; Enhancer Elements, Genetic; Cell Differentiation; Life Cycle Stages
PubMed: 37221124
DOI: 10.1016/j.tibs.2023.04.005 -
Genome Biology Apr 2024Epigenetic marks are reprogrammed during sexual reproduction. In flowering plants, DNA methylation is only partially remodeled in the gametes and the zygote. However,...
BACKGROUND
Epigenetic marks are reprogrammed during sexual reproduction. In flowering plants, DNA methylation is only partially remodeled in the gametes and the zygote. However, the timing and functional significance of the remodeling during plant gametogenesis remain obscure.
RESULTS
Here we show that DNA methylation remodeling starts after male meiosis in rice, with non-CG methylation, particularly at CHG sites, being first enhanced in the microspore and subsequently decreased in sperm. Functional analysis of rice CHG methyltransferase genes CMT3a and CMT3b indicates that CMT3a functions as the major CHG methyltransferase in rice meiocyte, while CMT3b is responsible for the increase of CHG methylation in microspore. The function of the two histone demethylases JMJ706 and JMJ707 that remove H3K9me2 may contribute to the decreased CHG methylation in sperm. During male gametogenesis CMT3a mainly silences TE and TE-related genes while CMT3b is required for repression of genes encoding factors involved in transcriptional and translational activities. In addition, CMT3b functions to repress zygotic gene expression in egg and participates in establishing the zygotic epigenome upon fertilization.
CONCLUSION
Collectively, the results indicate that DNA methylation is dynamically remodeled during male gametogenesis, distinguish the function of CMT3a and CMT3b in sex cells, and underpin the functional significance of DNA methylation remodeling during rice reproduction.
Topics: DNA Methylation; Oryza; Seeds; Methyltransferases; Gametogenesis; Gene Expression Regulation, Plant
PubMed: 38566207
DOI: 10.1186/s13059-024-03222-w -
Molecular Cell Apr 2024In mammals, dosage compensation involves two parallel processes: (1) X inactivation, which equalizes X chromosome dosage between males and females, and (2) X...
In mammals, dosage compensation involves two parallel processes: (1) X inactivation, which equalizes X chromosome dosage between males and females, and (2) X hyperactivation, which upregulates the active X for X-autosome balance. The field currently favors models whereby dosage compensation initiates "de novo" during mouse development. Here, we develop "So-Smart-seq" to revisit the question and interrogate a comprehensive transcriptome including noncoding genes and repeats in mice. Intriguingly, de novo silencing pertains only to a subset of Xp genes. Evolutionarily older genes and repetitive elements demonstrate constitutive Xp silencing, adopt distinct signatures, and do not require Xist to initiate silencing. We trace Xp silencing backward in developmental time to meiotic sex chromosome inactivation in the male germ line and observe that Xm hyperactivation is timed to Xp silencing on a gene-by-gene basis. Thus, during the gamete-to-embryo transition, older Xp genes are transmitted in a "pre-inactivated" state. These findings have implications for the evolution of imprinting.
Topics: Female; Mice; Male; Animals; X Chromosome Inactivation; Genomic Imprinting; Germ Cells; Epigenesis, Genetic; Embryo, Mammalian; RNA, Long Noncoding; X Chromosome; Mammals
PubMed: 38458200
DOI: 10.1016/j.molcel.2024.02.013 -
Cell Reports Jul 2023Pioneer transcription factors interact with nucleosomes to scan silent, compact chromatin, enabling cooperative events that modulate gene activity. While at a subset of...
Pioneer transcription factors interact with nucleosomes to scan silent, compact chromatin, enabling cooperative events that modulate gene activity. While at a subset of sites pioneer factors access chromatin by assisted loading with other transcription factors, the nucleosome-binding properties of pioneer factors enable them to initiate zygotic genome activation, embryonic development, and cellular reprogramming. To better understand nucleosome targeting in vivo, we assess whether pioneer factors FoxA1 and Sox2 target stable or unstable nucleosomes and find that they target DNase-resistant, stable nucleosomes, whereas HNF4A, a non-nucleosome binding factor, targets open, DNase-sensitive chromatin. Despite FOXA1 and SOX2 targeting similar proportions of DNase-resistant chromatin, using single-molecule tracking, we find that FOXA1 uses lower nucleoplasmic diffusion and longer residence times while SOX2 uses higher nucleoplasmic diffusion and shorter residence times to scan compact chromatin, while HNF4 scans compact chromatin much less efficiently. Thus, pioneer factors target compact chromatin through distinct processes.
Topics: Chromatin; Deoxyribonucleases; Nucleosomes; Protein Binding; Transcription Factors; Hepatocyte Nuclear Factor 3-alpha; SOXB1 Transcription Factors
PubMed: 37405916
DOI: 10.1016/j.celrep.2023.112748 -
Zygote (Cambridge, England) Aug 2023(), an evolutionarily distant homologue of the classical RNA-binding protein PUF (PUMILIO and FBF) family member, is also involved in the process of RNA metabolism...
(), an evolutionarily distant homologue of the classical RNA-binding protein PUF (PUMILIO and FBF) family member, is also involved in the process of RNA metabolism through post-transcriptional regulation. However, the functions of in mouse oocyte maturation and preimplantation embryonic development have not been elucidated. By comparing RNA levels in different tissues, we found that was widely expressed in multiple tissues, but moderately predominant in the ovary. Histochemical staining suggested that the PUM3 protein exhibits positive signals in oocytes, granulosa cells and theca cells of different follicle stages. Oocyte immunofluorescence results showed a slightly higher level of PUM3 protein in metaphase II compared with the germinal vesicle (GV) stage. After knockdown of in GV oocytes using siRNA injection (siPUM3), no obvious defect was observed in the processes of GV breakdown and polar body extrusion during maturation (IVM) for the oocytes. Compared with the control group, the group displayed no significant abnormality in the cleavage and blastocyst formation rate of these fertilized oocytes. Therefore, we can conclude that depletion of does not affect mouse oocyte maturation and early embryonic development .
Topics: Animals; Female; Mice; Pregnancy; Embryonic Development; In Vitro Oocyte Maturation Techniques; Oocytes; Oogenesis; RNA, Small Interfering
PubMed: 37194574
DOI: 10.1017/S0967199423000205 -
Cells Jan 2024Oogenesis is a developmental process leading to the formation of an oocyte, a haploid gamete, which upon fertilisation and sperm entry allows the male and the female... (Review)
Review
Oogenesis is a developmental process leading to the formation of an oocyte, a haploid gamete, which upon fertilisation and sperm entry allows the male and the female pronuclei to fuse and give rise to a zygote. In addition to forming a haploid gamete, oogenesis builds up a store of proteins, mRNAs, and organelles in the oocyte needed for the development of the future embryo. In several species, such as , the polarity axes determinants of the future embryo must be asymmetrically distributed prior to fertilisation. In the oocyte, the correct positioning of the nucleus is essential for establishing the dorsoventral polarity axis of the future embryo and allowing the meiotic spindles to be positioned in close vicinity to the unique sperm entry point into the oocyte.
Topics: Animals; Male; Female; Drosophila; Semen; Oogenesis; Oocytes; Cell Nucleus
PubMed: 38275826
DOI: 10.3390/cells13020201 -
Zygote (Cambridge, England) Feb 2024The global transition towards diets high in calories has contributed to 2.1 billion people becoming overweight, or obese, which damages male reproduction and harms...
The global transition towards diets high in calories has contributed to 2.1 billion people becoming overweight, or obese, which damages male reproduction and harms offspring. Recently, more and more studies have shown that paternal exposure to stress closely affects the health of offspring in an intergenerational and transgenerational way. SET Domain Containing 2 (), a key epigenetic gene, is highly conserved among species, is a crucial methyltransferase for converting histone 3 lysine 36 dimethylation (H3K36me2) into histone 3 lysine 36 trimethylation (H3K36me3), and plays an important regulator in the response to stress. In this study, we compared patterns of SETD2 expression and the H3K36me3 pattern in pre-implantation embryos derived from normal or obese mice induced by high diet. The results showed that mRNA was significantly higher in the high-fat diet (HFD) group than the control diet (CD) group at the 2-cell, 4-cell, 8-cell, and 16-cell stages, and at the morula and blastocyst stages. The relative levels of H3K36me3 in the HFD group at the 2-cell, 4-cell, 8-cell, 16-cell, morula stage, and blastocyst stage were significantly higher than in the CD group. These results indicated that dietary changes in parental generation (F0) male mice fed a HFD were traceable in 2/H3K36me3 in embryos, and that a paternal high-fat diet brings about adverse effects for offspring that might be related to SETD2/H3K36me3, which throws new light on the effect of paternal obesity on offspring from an epigenetic perspective.
Topics: Humans; Male; Animals; Mice; Histones; Diet, High-Fat; Lysine; Obesity; Embryonic Development
PubMed: 38018398
DOI: 10.1017/S0967199423000448