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Emerging evidence has linked the dysregulation of N 6 -methyladenosine (m 6 A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of m 6 A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1–associated protein (WTAP), a key component of the “writer” complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of m 6 A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of m 6 A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response. Further, a myeloid deficiency in WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of the m 6 A writer complex to reduce the global m 6 A levels by targeting the phase separation of WTAP may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N6‐methyladenosine (m6A), the most abundant mammalian mRNA modification. However, which and how gut microbiota‐derived metabolites reprogram host transcriptome and m6A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota‐derived metabolites impact host transcriptome and m6A epitranscriptome using multiple mouse models and multi‐omics approaches. Various antibiotics‐induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ‐free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid‐producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m6A epitranscriptome in multiple tissues. Mechanistically, the expression of m6A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m6A biology. Collectively, these results demonstrate that antibiotic‐induced gut dysbiosis regulates the landscape of host transcriptome and m6A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression. Yang et al. report that gut dysbiosis induced by antibiotics can lead to tissue‐specific reprogramming of host transcriptome and epitranscriptome via alterations in bile acid metabolism. Mechanistically, it is shown that m6A writers are regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m6A biology.

The host microbiome plays an important role in regulating physiology through microbiota-derived metabolites during host-microbiome interactions. However, molecular mechanism underly host-microbiome interactions remains to be explored. In this study, we used Drosophila as the model to investigate the influence of microbiome and microbiota-derived metabolite sodium butyrate on host transcriptome and metabolome. We established both a sterile Drosophila model and a conventional Drosophila model to demonstrate the role of sodium butyrate. Using multi-omics analysis, we found that microbiome and sodium butyrate could impact host gene expression patterns in both the sterile Drosophila model and the conventional Drosophila model. The analysis of gut microbial using 16S rRNA sequencing showed sodium butyrate treatment also influenced Drosophila bacterial structures. In addition, Drosophila metabolites identified by ultra-high performance liquid chromatography-MS/MS were shown to be affected by sodium butyrate treatment with lipids as the dominant changed components. Our integrative analysis of the transcriptome, the microbiome, and the metabolome data identified candidate transcripts that are coregulated by sodium butyrate. Taken together, our results reveal the impact of the microbiome and microbiota-derived sodium butyrate on host transcriptome and metabolome, and our work provides a better understanding of host-microbiome interactions at the molecular level with multi-omics data.

Emerging evidence has linked the dysregulation of [N.sup.6]-methyladenosine ([m.sup.6] A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of [m.sup.6]A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1-associated protein (WTAP), a key component of the \"writer\" complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of [m.sup.6]A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of [m.sup.6]A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response. Further, a myeloid deficiency in WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk- increasing mechanism, and interrupting the assembly of the [m.sup.6]A writer complex to reduce the global [m.sup.6]A levels by targeting the phase separation of WTAP may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N 6 ‐methyladenosine (m 6 A), the most abundant mammalian mRNA modification. However, which and how gut microbiota‐derived metabolites reprogram host transcriptome and m 6 A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota‐derived metabolites impact host transcriptome and m 6 A epitranscriptome using multiple mouse models and multi‐omics approaches. Various antibiotics‐induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ‐free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid‐producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m 6 A epitranscriptome in multiple tissues. Mechanistically, the expression of m 6 A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m 6 A biology. Collectively, these results demonstrate that antibiotic‐induced gut dysbiosis regulates the landscape of host transcriptome and m 6 A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression.

Emerging evidence has linked dysregulation of N6-methyladenosine (m6A) to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high m6A modification in a variety of hyperinflammatory states is p65-dependent, because Wilms tumor 1 associated protein (WTAP), a key component of the writer complex, is transcriptionally regulated by p65 and its overexpression can lead to higher m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of “writer” complex to nuclear speckles and the deposition of m6A marks onto transcriptionally active inflammatory transcripts, thereby accelerating proinflammatory response. Furthermore, myeloid deficiency of WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of m6A writer complex by targeting the phase separation of WTAP to reduce the global m6A level may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

Bri1-EMS Suppressor 1 (BES1) and Brassinazole Resistant 1 (BZR1) are two key transcription factors in the brassinosteroid (BR) signaling pathway, serving as crucial integrators that connect various signaling pathways in plants. Extensive genetic and biochemical studies have revealed that BES1 and BZR1, along with other protein factors, form a complex interaction network that governs plant growth, development, and stress tolerance. Among the interactome of BES1 and BZR1, several proteins involved in posttranslational modifications play a key role in modifying the stability, abundance, and transcriptional activity of BES1 and BZR1. This review specifically focuses on the functions and regulatory mechanisms of BES1 and BZR1 protein interactors that are not involved in the posttranslational modifications but are crucial in specific growth and development stages and stress responses. By highlighting the significance of the BZR1 and BES1 interactome, this review sheds light on how it optimizes plant growth, development, and stress responses.

Brassinosteroids (BRs) play vital roles in the plant life cycle and synthetic BRs are widely used to increase crop yield and plant stress tolerance. Among them are 24R-methyl-epibrassinolide (24-EBL) and 24S-ethyl-28-homobrassinolide (28-HBL), which differ from brassinolide (BL, the most active BR) at the C-24 position. Although it is well known that 24-EBL is 10% active as BL, there is no consensus on the bioactivity of 28-HBL. A recent outpouring of research interest in 28-HBL on major crops accompanied with a surge of industrial-scale synthesis that produces mixtures of active (22R,23R)-28-HBL and inactive (22S,23S)-28HBL, demands a standardized assay system capable of analyzing different synthetic “28-HBL” products. In this study, the relative bioactivity of 28-HBL to BL and 24-EBL, including its capacity to induce the well-established BR responses at molecular, biochemical, and physiological levels, was systematically analyzed using the whole seedlings of the wild-type and BR-deficient mutant of Arabidopsis thaliana. These multi-level bioassays consistently showed that 28-HBL exhibits a much stronger bioactivity than 24-EBL and is almost as active as BL in rescuing the short hypocotyl phenotype of the dark-grown det2 mutant. These results are consistent with the previously established structure–activity relationship of BRs, proving that this multi-level whole seedling bioassay system could be used to analyze different batches of industrially produced 28-HBL or other BL analogs to ensure the full potential of BRs in modern agriculture.