Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P4) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P4 signaling. Conditional deletion of methyltransferase-like 3 (Mettl3), encoding the m6A writer METTL3, in the female reproductive tract using a Cre mouse line with Pgr promoter (Pgr-Cre) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of Mettl3 null mice failed to respond to artificial decidualization. We further found that Mettl3 deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that Pgr mRNA is a direct target for METTL3-mediated m6A modification. A luciferase assay revealed that the m6A modification in the 5' untranslated region (5'-UTR) of Pgr mRNA enhances PGR protein translation efficiency in a YTHDF1-dependent manner. Finally, we demonstrated that METTL3 is required for human endometrial stromal cell decidualization in vitro and that the METTL3-PGR axis is conserved between mice and humans. In summary, this study provides evidence that METTL3 is essential for normal P4 signaling during embryo implantation via m6A-mediated translation control of Pgr mRNA.
Progesterone , Receptors, Progesterone , Female , Mice , Humans , Animals , Progesterone/metabolism , Receptors, Progesterone/genetics , Receptors, Progesterone/metabolism , Embryo Implantation/genetics , Uterus/metabolism , Methyltransferases/genetics , Methyltransferases/metabolism , Mice, Knockout , RNA, Messenger/metabolism
Using coarse-grained molecular dynamic simulations, we systematically investigate the conformational transitions of a helical polymer chain under tension. While a typical helix-coil transition is derived by our simulation with the absence of the stretching and varying temperature, the chain behaviors become more interesting and complicated when the force is applied. Specifically, when the temperature is low enough relative to the chain rigidity, the polymer is solid-like and displays a series of stepwise conformational transitions on the force-extension curve. We introduce a chain disorder parameter to capture the essence of these transitions. Detailed investigation indicates that the first few transitions correspond to the breaking of the helices, while the last one denotes a transition from a fully disordered state to an all-trans ordered conformation. By increasing the temperature, the thermal fluctuation makes the chain enter a liquid-like state, in which the initial weak stretching induces extra helix formation, followed by the force-induced helix breaking and the transition to the all-trans state. In contrast to the solid-like state, the liquid-like chain always adopts a mixed conformation with both helical and disordered regions. Further increasing the temperature makes the chain fully flexible and thus no helices can form at such a gas-like stage. We further study the relaxation behaviors of the polymer by decreasing the force and find hysteresis for the solid-like cases. Finally, we compare our simulation results with experiments in a semi-quantitative fashion and get quite good agreement.
Although the volume transition of the polyelectrolyte gel has been studied for decades, less study on the finite size effects of the mobile ions has been conducted. In the present paper, Tanaka's classical theory of polyelectrolyte gel is extended to the cases of mobile ions of finite volume. In the salt free limit, the theoretical results show that the discontinuous volume transition of the polyelectrolyte gel will become a continuous one for counterionic size larger than a critical value. When a significant amount of salt is added, the critical value for the volume transition increases as a result of electrostatic screening. An increase in salt concentration can also make the polyelectrolyte gel in poor solvent collapse. Poorer solvent is needed to trigger the salt-induced collapse in polyelectrolyte gel with larger mobile ions than that with smaller ones. The effects of ionic size on the critical points and phase diagram of the volume transition are also discussed. The theoretical results suggest that the swelling behavior of polyelectrolyte gel might be tuned with salt of different volumes.
Self-consistent field theory (SCFT) calculation has been performed to study the structure and stimuli-responsive behaviors of diblock polyampholyte (PA) brushes. Two kinds of brushes are considered: one formed by PA chains consisting of two strong polyelectrolyte blocks (system i) and the other formed by PA chains of a grafted strong acid block and an ungrafted weak base block (system ii). Density profiles and brush thickness are obtained. The chain trajectory (average position of each polymer segment) is also calculated to characterize the conformation of the grafted chains. For system i, the ungrafted blocks loop backward at low salt concentration and extend out at high salt concentration. For system ii, the charge fraction of the annealing block is independent of pH and becomes dependent on it at high salt concentration. As a result, pH has no effect on the brush structure at low salt concentration and takes effect at high salt concentration. That the salt concentration can switch on and off the responses of the PA brush to the pH stimuli may find application in building functional surfaces.
