Trascription factor TEAD4 is not required for bovine blastocyst formation

Departamento de Reproducción animalPeer reviewe

Early sex-dependent differences in response to environmental stress

Developmental plasticity enables the appearance of long-term effects in offspring caused by exposure to environmental stressors during embryonic and foetal life. These long-term effects can be traced to pre- and post-implantation development, and in both cases, the effects are usually sex specific. During preimplantation development, male and female embryos exhibit an extensive transcriptional dimorphism mainly driven by incomplete X chromosome inactivation. These early developmental stages are crucial for the establishment of epigenetic marks that will be conserved throughout development, making it a particularly susceptible period for the appearance of long-term epigenetic-based phenotypes. Later in development, gonadal formation generates hormonal differences between the sexes, and male and female placentae exhibit different responses to environmental stressors. The maternal environment, including hormones and environmental insults during pregnancy, contributes to sex-specific placental development that controls genetic and epigenetic programming during foetal development, regulating sex-specific differences, including sex-specific epigenetic responses to environmental hazards, leading to long-term effects. This review summarizes several human and animal studies examining sex-specific responses to environmental stressors during both the periconception period (caused by differences in sex chromosome dosage) and placental development (caused by both sex chromosomes and hormones). The identification of relevant sex-dependent trajectories caused by sex chromosomes and/or sex hormones is essential to define diagnostic markers and prevention/intervention protocols

The oviduct From sperm selection to the epigenetic landscape of the embryo

The mammalian oviduct is the place where life begins as it is the site of fertilization and preimplantation embryo development. Recent research has highlighted the important role played by the oviduct both in sperm selection for natural fertilization and in the genetic and epigenetic reprogramming of preimplantation embryo development. This review examines oviduct fluid composition with a special emphasis on exosomes and the role played by the oviduct in sperm selection, early embryo development, and in reshaping the epigenetic landscape of the embryo. In addition, the implications of data obtained for improving assisted reproductive technologies are discussed

Tet-mediated imprinting erasure in H19 locus following reprogramming of spermatogonial stem cells to induced pluripotent stem cells

Selective methylation of CpG islands at imprinting control regions (ICR) determines the monoparental expression of a subset of genes. Currently, it is unclear whether artificial reprogramming induced by the expression of Yamanaka factors disrupts these marks and whether cell type of origin affects the dynamics of reprogramming. In this study, spermatogonial stem cells (SSC) that harbor paternalized imprinting marks, and fibroblasts were reprogrammed to iPSC (SSCiPSC and fiPSC). The SSCiPSC were able to form teratomas and generated chimeras with a higher skin chimerism than those derived from fiPSC. RNA-seq revealed extensive reprogramming at the transcriptional level with 8124 genes differentially expressed between SSC and SSCiPSC and only 490 between SSCiPSC and fiPSC. Likewise, reprogramming of SSC affected 26 of 41 imprinting gene clusters known in the mouse genome. A closer look at H19 ICR revealed complete erasure in SSCiPSC in contrast to fiPSC. Imprinting erasure in SSCiPSC was maintained even after in vivo differentiation into teratomas. Reprogramming of SSC from Tet1 and Tet2 double knockout mice however lacked demethylation of H19 ICR. These results suggest that imprinting erasure during reprogramming depends on the epigenetic landscape of the precursor cell and is mediated by TETs at the H19 locus

Potential health risks associated to ICSI Insights from animal models and strategies for a safe procedure

Artificial reproductive techniques are currently responsible for 1.7-4% of the births in developed countries and intracytoplasmatic sperm injection (ICSI) is the most commonly used, accounting for 70-80% of the cycles performed. Despite being an invaluable tool for infertile couples, the technique bypasses several biological barriers that naturally select the gametes to achieve an optimal embryonic and fetal development. In this perspective, ICSI has been associated with an increased risk for diverse health problems, ranging from premature births and diverse metabolic disorders in the offspring to more severe complications such as abortions, congenital malformations, and imprinting disorders. In this review, we discuss the possible implications of the technique per se on these adverse outcomes and highlight the importance of several experiments using mammalian models to truthfully test these implications and to uncover the molecular base that origins these health problems. We also dissect the specific hazards associated to ICSI and describe some strategies that have been developed to mimic the gamete selection occurring in natural conception in order to improve the safety of the procedure. © 2014 Sánchez-Calabuig, López-Cardona, Fernández-González, Ramos-Ibeas, FonsecaBalvís, Laguna-Barraza, Pericuesta, Gutiérrez-Adánand Bermejo-álvarez

Sex-specific embryonic origin of postnatal phenotypic variability

Preimplantation developmental plasticity has evolved in order to offer the best chances of survival under changing environments. Conversely, environmental conditions experienced in early life can dramatically influence neonatal and adult biology, which may result in detrimental long-term effects. Several studies have shown that small size at birth, which is associated with a greater risk of metabolic syndrome, is largely determined before the formation of the blastocysts because 70%-80% of variation in bodyweight at birth has neither a genetic nor environmental component. In addition, it has been reported that adult bodyweight is programmed by energy-dependent process during the pronuclear stage in the mouse. Although the early embryo has a high developmental plasticity and adapts and survives to adverse environmental conditions, this adaptation may have adverse consequences and there is strong evidence that in vitro culture can be a risk factor for abnormal fetal outcomes in animals systems, with growing data suggesting that a similar link may be apparent for humans. In this context, male and female preimplantation embryos display sex-specific transcriptional and epigenetic regulation, which, in the case of bovine blastocysts, expands to one-third of the transcripts detected through microarray analysis. This sex-specific bias may convert the otherwise buffered stochastic variability in developmental networks in a sex-determined response to the environmental hazard. It has been widely reported that environment can affect preimplantation development in a sex-specific manner, resulting in either a short-term sex ratio adjustment or in long-term sex-specific effects on adult health. The present article reviews current knowledge about the natural phenotypic variation caused by epigenetic mechanisms and the mechanisms modulating sex-specific changes in phenotype during early embryo development resulting in sex ratio adjustments or detrimental sex-specific consequences for adult health. Understanding the natural embryo sexual dimorphism for programming trajectories will help understand the early mechanisms of response to environmental insults. © 2013 IETS

Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models

Flaviviruses are (re)-emerging RNA viruses strictly dependent on lipid metabolism for infection. In the search for host targeting antivirals, we explored the effect of pharmacological modulation of fatty acid metabolism during flavivirus infection. Considering the central role of acetyl-Coenzyme A carboxylase (ACC) on fatty acid metabolism, we analyzed the effect of three small-molecule ACC inhibitors (PF-05175157, PF-05206574, and PF-06256254) on the infection of medically relevant flaviviruses, namely West Nile virus (WNV), dengue virus, and Zika virus. Treatment with these compounds inhibited the multiplication of the three viruses in cultured cells. PF-05175157 induced a reduction of the viral load in serum and kidney in WNV-infected mice, unveiling its therapeutic potential for the treatment of chronic kidney disease associated with persistent WNV infection. This study constitutes a proof of concept of the reliability of ACC inhibitors to become viable antiviral candidates. These results support the repositioning of metabolic inhibitors as broad-spectrum antivirals.This work was supported by Spanish Ministry of Economy and Competitiveness (MINECO) Fondo Europeo de Desarrollo Regional (FEDER) under Grant AGL2014-56518-JIN to M.A.M-A; INIA under Grant RTA2015-009 to J.-C.S.; and the Comunidad Autónoma de Madrid under Grant P2013/ABI-2906 (PLATESA) to J.-C.S and F.S. We thank the Pfizer Compound Transfer Program (Grants WI215864 and WI201531 to M.A.M.-A.) for providing the ACC inhibitors for cell culture and in vivo assays.Peer reviewe