Human transcriptional enhanced associate domain (TEAD) family consists of four paralogous transcription factors that function to modulate gene expression by interacting with YAP‐like coactivators and have been recognized as potential therapeutic targets of diverse diseases including lung cancer and gastric tumor. Here, we attempt to explore the systematic interaction profile between the 4 TEAD proteins and the peptides derived from the binding sites of 8 known YAP‐like coactivators, in order to analyze the binding affinity and recognition specificity of these peptides toward the TEAD family, and to design hydrocarbon‐stapled/cyclized peptides that can target the specific interaction profile for each coactivator. Structural, energetic, and dynamic investigations of TEAD–coactivator interactions reveal that the coactivators adopt three independent secondary structure regions (β‐strand, α‐helix, and Ω‐loop) to surround on the surface of TEAD proteins, in which the α‐helical and Ω‐loop regions are primarily responsible for the interactions. Five α‐helical peptides and four Ω‐loop peptides are derived from the 8 YAP‐like coactivators, and their systematic binding profile toward the 4 TEAD proteins is created, and hydrocarbon stapling and cyclization strategies are employed to constrain the free α‐helical and Ω‐loop peptides into their native conformations, respectively, thus effectively promoting peptide binding to TEADs. The all‐hydrocarbon and disulfide bridges are designed to point out the TEAD–peptide complex interface, which would not disrupt the direct intermolecular interaction between the TEAD and peptide. Therefore, the stapling and cyclization only improve peptide binding affinity to these TEADs, but do not alter peptide recognition specificity over different TEADs.

The fermentation of endophytic Nigrospora chinensis GGY-3 resulted in the isolation of tropolone stipitaldehyde (1), which exhibited broad-spectrum inhibition activity against fungi and bacteria, especially against Phytophthora capsici, with an EC50 value of 0.83 μg/mL and Xanthomonas oryzae pv. oryzicola, with a minimum inhibitory concentration value of 4.0 μg/mL. The in vitro and in vivo assays demonstrated that 1 had a significant protective effect on P. capsici. Furthermore, 1 inhibited the spore germination of P. capsici and damaged the plasma membrane structure. As observed by SEM and TEM, after exposure to 1, mycelia exhibited swelling, shrunken, branch-increasing phenomena, cell wall and membrane damage, and disordered content. Transcriptome analysis revealed that 1 might affect starch and sucrose metabolism and fatty acid biosynthesis by suppressing the expression of genes relevant to cell wall synthetases and cell membrane-associated genes. These findings indicate that 1 may be a potential agrochemical fungicide for controlling phytophthora blight.

H3K27me3 is an epigenetic modification that results in the repression of gene transcription. The transcription factor RUNX1 (the runt-related transcription factor 1) influences granulosa cells’ growth and ovulation. This research uses ELISA, flow cytometry, EDU, ChIP-PCR, WB and qPCR to investigate steroidogenesis, cell apoptosis, and the proliferation effect of RUNX1 in porcine granulosa cells (pGCs) as regulated by H3K27me3. Decreased H3K27me3 stimulates the expression of steroidogenesis-related genes, including CYP11A1, PTGS2, and STAR, as well as prostaglandin. H3K27me3 transcriptionally represses RUNX1 here, whereas RUNX1 acts as an activator of FSHR, CYP11A1, and CYP19A1, promoting the production of androgen, estrogen, and prostaglandin, as well as increasing anti-apoptotic and cell proliferation activity, but decreasing progesterone. Both the complementary recovery of the H3K27me3 antagonist with the siRUNX1 signal, and the H3K27me3 agonist with the RUNX1 signal to maintain RUNX1 lead to the activation of CYP19A1, ER1, HSD17β4, and STAR here. Androgen and prostaglandin are significantly repressed but progesterone is markedly increased with the antagonist and siRUNX1. Prostaglandin is significantly promoted with the agonist and RUNX1. Furthermore, H3K27me3-RUNX1 affects the anti-apoptotic activity and stimulation of proliferation in pGCs. The present work verifies the transcriptional suppression of RUNX1 by H3K27me3 during antral follicular development and maturation, which determines the levels of hormone synthesis and cell apoptosis and proliferation in the pGC microenvironment.

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