Regulation of Host Chromatin by Bacterial Metabolites

Mani, Sridhar

doi:10.1016/b978-0-12-802389-1.00023-x

Cited by 5 publications

(5 citation statements)

References 231 publications

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“…We have previously shown that PXR activation down‐regulates TLR4 mRNA expression, leading to the inhibition of NF‐κB signaling (Venkatesh et al , ; Mani, ; Ranhotra et al , ). We have also shown that FKK5 and FKK6 directly interact with and activate PXR‐LBD.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, to determine the effect of FKK5 and FKK6 on the PXR‐TLR4‐NF‐κB signaling pathway, we used PXR‐transfected Caco‐2 cells. Undifferentiated Caco‐2 cells inherently have low PXR expression (not detected) but relatively higher TLR4 expression and are excellent in vitro models for the study of enterocyte function (Delie & Rubas, ; Mani, ; Ranhotra et al , ; Hung & Suzuki, ). FKK5 and FKK6 down‐regulated TLR4 (0.39‐fold and 0.49‐fold, respectively) but up‐regulated CYP3A4 (3.7‐fold and 3.29‐fold, respectively) and MDR1 (5.12‐fold and 6.45‐fold, respectively) mRNA expression (Fig b) (see Materials and Methods, Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…These cells are well‐established models to study intestinal cell differentiation and physiology, specifically under conditions of inflammatory stimuli (Hung & Suzuki, ). Differentiated Caco‐2 cells following long‐term culture have increased PXR expression (Mani, ). In these cells, TNF‐α significantly induced IL‐8 mRNA; however, only FKK6 (25 μM) significantly reduced cytokine‐induced IL‐8 (Fig A).…”

Section: Resultsmentioning

confidence: 99%

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Targeting the pregnane X receptor using microbial metabolite mimicry

et al. 2020

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The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off‐target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first‐in‐class non‐cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR‐specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro‐inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Targeting the pregnane X receptor using microbial metabolite mimicry

et al. 2020

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“…The general importance of histone modifications in host-microbe interactions has been acknowledged in plants, humans, and other invertebrates [16][17][18]. Through chemical signals and metabolites, endosymbionts can influence epigenomes of host cells and directly enable communication between the two partners [18,41]. Interestingly, histone acetylase and deacetylase activity have been shown to be influenced by microbes and dietary factors [10,42,43].…”

Section: Discussionmentioning

confidence: 99%

Histone modifications and DNA methylation act cooperatively in regulating symbiosis genes in the sea anemone Aiptasia

et al. 2022

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Background The symbiotic relationship between cnidarians and dinoflagellates is one of the most widespread endosymbiosis in our oceans and provides the ecological basis of coral reef ecosystems. Although many studies have been undertaken to unravel the molecular mechanisms underlying these symbioses, we still know little about the epigenetic mechanisms that control the transcriptional responses to symbiosis. Results Here, we used the model organism Exaiptasia diaphana to study the genome-wide patterns and putative functions of the histone modifications H3K27ac, H3K4me3, H3K9ac, H3K36me3, and H3K27me3 in symbiosis. While we find that their functions are generally conserved, we observed that colocalization of more than one modification and or DNA methylation correlated with significantly higher gene expression, suggesting a cooperative action of histone modifications and DNA methylation in promoting gene expression. Analysis of symbiosis genes revealed that activating histone modifications predominantly associated with symbiosis-induced genes involved in glucose metabolism, nitrogen transport, amino acid biosynthesis, and organism growth while symbiosis-suppressed genes were involved in catabolic processes. Conclusions Our results provide new insights into the mechanisms of prominent histone modifications and their interaction with DNA methylation in regulating symbiosis in cnidarians.

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“…The general importance of histone modifications in host-microbe interactions has been acknowledged in plants, humans, and other invertebrates 16–18 . Through chemical signals and metabolites, endosymbionts can influence epigenomes of host cells and directly enable communication between the two partners 18, 40 . Interestingly, histone acetylase and deacetylase activity have been shown to be influenced by microbes and dietary factors 15, 41, 42 .…”

Section: Discussionmentioning

confidence: 99%

Histone modifications and DNA methylation act cooperatively in regulating symbiosis genes in the sea anemone Aiptasia

Nawaz

Cziesielski

Mariappan

et al. 2022

Preprint

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The symbiotic relationship between cnidarians and dinoflagellates is one of the most widespread endosymbiosis in our oceans and provides the ecological basis of coral-reef ecosystems. Although many studies have been undertaken to unravel the molecular mechanisms underlying these symbioses, we still know little about the epigenetic mechanisms that control the transcriptional responses to symbiosis. Here, we used the model organism Exaiptasia diaphana to study the genome-wide patterns and putative functions of the histone modifications H3K27ac, H3K4me3, H3K9ac, H3K36me3 and H3K27me3 in symbiosis. While we find that their functions are generally conserved, we observed that colocalization of more than one modification and or DNA methylation correlated with significantly higher gene expression, suggesting a cooperative action of histone modifications and DNA methylation in promoting gene expression. Analysis of symbiosis genes revealed that activating histone modifications predominantly associated with symbiosis induced genes involved in glucose metabolism, nitrogen transport, amino acid biosynthesis and organism growth while symbiosis suppressed genes were involved in catabolic processes. Our results provide new insights into the mechanisms of prominent histone modifications and their interaction with DNA methylation in regulating symbiosis in cnidarians.

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Regulation of Host Chromatin by Bacterial Metabolites

Cited by 5 publications

References 231 publications

Targeting the pregnane X receptor using microbial metabolite mimicry

Targeting the pregnane X receptor using microbial metabolite mimicry

Histone modifications and DNA methylation act cooperatively in regulating symbiosis genes in the sea anemone Aiptasia

Histone modifications and DNA methylation act cooperatively in regulating symbiosis genes in the sea anemone Aiptasia

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