SUMMARYIn female mice, two forms of X chromosome inactivation (XCI) ensure the selective silencing of female sex chromosomes during mouse embryogenesis. Beginning at the four cell stage, imprinted XCI (iXCI) exclusively silences the paternal X (Xp). Later, around implantation, epiblast cells of the ICM that give rise to the embryo reactivate the Xp and undergo a random form of XCI (rXCI)1,2. Xist, a long non-coding RNA crucial for both forms of XCI, is activated by the ubiquitin ligase Rnf12/RLIM3-5. While Rnf12/RLIM is required for triggering iXCI in mice, its importance for rXCI has been controversial. Here, we show that Rnf12/RLIM levels are downregulated in embryonic cells undergoing rXCI. Using mouse genetics we demonstrate that female cells lacking Rnf12/RLIM from pre-implantation stages onwards display hallmarks of XCI including Xist clouds and H3K27me3 foci and display full embryogenic potential. These results provide evidence that Rnf12/RLIM is dispensable for rXCI, indicating that in mice an Rnf12/RLIM-independent mechanism activates Xist in the embryo proper.
Long noncoding RNAs (lncRNAs) exhibit diverse functions, including regulation of development. Here we combine genome-wide mapping of SMAD3 occupancy with expression analysis to identify lncRNAs induced by activin signaling during endoderm differentiation of human embryonic stem cells (hESCs). We find that DIGIT is divergent to Goosecoid (GSC) and expressed during endoderm differentiation. Deletion of the SMAD3-occupied enhancer proximal to DIGIT inhibits DIGIT and GSC expression and definitive endoderm differentiation. Disruption of the gene encoding DIGIT and depletion of the DIGIT transcript reveal that DIGIT is required for definitive endoderm differentiation. In addition, we identify the mouse ortholog of DIGIT and show that it is expressed during development and promotes definitive endoderm differentiation of mouse ESCs. DIGIT regulates GSC in trans, and activation of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient hESCs. Our study defines DIGIT as a conserved noncoding developmental regulator of definitive endoderm.
BackgroundInfertility is a common reproductive disorder, with male factor infertility accounting for approximately half of all cases. Taking a paternal perceptive, recent research has shown that sperm epigenetics, such as changes in DNA methylation, histone modification, chromatin structure, and noncoding RNA expression, can impact reproductive and offspring health. Importantly, environmental conditions during the preconception period has been demonstrated to shape sperm epigenetics.ObjectivesTo provide an overview on epigenetic modifications that regulate normal gene expression and epigenetic remodeling that occurs during spermatogenesis, and to discuss the epigenetic alterations that may occur to the paternal germline as a consequence of preconception environmental conditions and exposures.Materials and methodsWe examined published literature available on databases (PubMed, Google Scholar, ScienceDirect) focusing on adult male preconception environmental exposures and sperm epigenetics in epidemiologic studies and animal models.ResultsThe preconception period is a sensitive developmental window in which a variety of exposures such as toxicants, nutrition, drugs, stress, and exercise, affects sperm epigenetics.Discussion and ConclusionUnderstanding the environmental legacy of the sperm epigenome during spermatogenesis will enhance our understanding of reproductive health and improve reproductive success and offspring well‐being.
Successful mammalian development requires descendants of single-cell zygotes to differentiate into diverse cell types even though they contain the same genetic material. Preimplantation dynamics are first driven by the necessity of reprogramming haploid parental epigenomes to reach a totipotent state. This process requires extensive erasure of epigenetic marks shortly after fertilization. During the few short days after formation of the zygote, epigenetic programs are established and are essential for the first lineage decisions and differentiation. Here we review the current understanding of DNA methylation and histone modification dynamics responsible for these early changes during mammalian preimplantation development. In particular we highlight insights that have been gained through next generation sequencing technologies comparing human embryos to other models as well as the recent discoveries of active DNA demethylation mechanisms at play during preimplantation.
Parental age at time of offspring conception is increasing in developed countries. Advanced male age is associated with decreased reproductive success and increased risk of adverse neurodevelopmental outcomes in offspring. Mechanisms for these male age effects remain unclear, but changes in sperm DNA methylation over time is one potential explanation. We assessed genome-wide methylation of sperm DNA from 47 semen samples collected from male participants of couples seeking infertility treatment. We report that higher male age was associated with lower likelihood of fertilization and live birth, and poor embryo development (p < 0.05). Furthermore, our multivariable linear models showed male age was associated with alterations in sperm methylation at 1698 CpGs and 1146 regions (q < 0.05), which were associated with > 750 genes enriched in embryonic development, behavior and neurodevelopment among others. High dimensional mediation analyses identified four genes (DEFB126, TPI1P3, PLCH2 and DLGAP2) with age-related sperm differential methylation that accounted for 64% (95% CI 0.42–0.86%; p < 0.05) of the effect of male age on lower fertilization rate. Our findings from this modest IVF population provide evidence for sperm methylation as a mechanism of age-induced poor reproductive outcomes and identifies possible candidate genes for mediating these effects.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.