bims-meprid 2021-07-11 papers

Hepatology. 2021 Jul 07.

Global Microbiota-Dependent Histone Acetylation Patterns are Irreversible and Independent of Short Chain Fatty Acids.

Yedidya Saiman, Ting-Chin David Shen, Peder J Lund, Victoria M Gershuni, Cholsoon Jang, Shivali Patel, Sunhee Jung, Emma E Furth, Elliot S Friedman, Lillian Chau, Benjamin A Garcia, Gary D Wu.

Although germ-free mice are an indispensable tool in studying the gut microbiome and its effects on host physiology, they are phenotypically different than their conventional counterparts. While antibiotic-mediated microbiota depletion in conventional mice leads to physiologic alterations that often mimic the germ-free state, the degree to which the effects of microbial colonization on the host are reversible is unclear. The gut microbiota produces abundant short chain fatty acids (SCFAs) and previous studies have demonstrated a link between microbial derived SCFAs and global hepatic histone acetylation in germ-free mice. We demonstrate that global hepatic histone acetylation states measured by mass spectrometry remained largely unchanged despite loss of luminal and portal vein SCFAs after antibiotic-mediated microbiota depletion. In contrast to stable hepatic histone acetylation states, we see robust hepatic transcriptomic alterations after microbiota depletion. Additionally, neither dietary supplementation with supraphysiologic levels of SCFA nor the induction of hepatocyte proliferation in the absence of microbiota-derived SCFAs led to alterations in global hepatic histone acetylation. In conclusion, these results suggest that microbiota-dependent landscaping of the hepatic epigenome via global histone acetylation is static in nature while the hepatic transcriptome is responsive to alterations in the gut microbiota.

Keywords: Antibiotic-treated mice; Epigenetics; Germ free mice; Liver disease; Microbiome

DOI: https://doi.org/10.1002/hep.32043

Nat Commun. 2021 Jul 07. 12(1): 4173

Hexosamine biosynthetic pathway and O-GlcNAc-processing enzymes regulate daily rhythms in protein O-GlcNAcylation.

Xianhui Liu, Ivana Blaženović, Adam J Contreras, Thu M Pham, Christine A Tabuloc, Ying H Li, Jian Ji, Oliver Fiehn, Joanna C Chiu.

The integration of circadian and metabolic signals is essential for maintaining robust circadian rhythms and ensuring efficient metabolism and energy use. Using Drosophila as an animal model, we show that cellular protein O-GlcNAcylation exhibits robust 24-hour rhythm and represents a key post-translational mechanism that regulates circadian physiology. We observe strong correlation between protein O-GlcNAcylation rhythms and clock-controlled feeding-fasting cycles, suggesting that O-GlcNAcylation rhythms are primarily driven by nutrient input. Interestingly, daily O-GlcNAcylation rhythms are severely dampened when we subject flies to time-restricted feeding at unnatural feeding time. This suggests the presence of clock-regulated buffering mechanisms that prevent excessive O-GlcNAcylation at non-optimal times of the day-night cycle. We show that this buffering mechanism is mediated by the expression and activity of GFAT, OGT, and OGA, which are regulated through integration of circadian and metabolic signals. Finally, we generate a mathematical model to describe the key factors that regulate daily O-GlcNAcylation rhythm.

DOI: https://doi.org/10.1038/s41467-021-24301-7

Cell. 2021 Jun 25. pii: S0092-8674(21)00708-X. [Epub ahead of print]

Polyamine metabolism is a central determinant of helper T cell lineage fidelity.

Polyamine synthesis represents one of the most profound metabolic changes during T cell activation, but the biological implications of this are scarcely known. Here, we show that polyamine metabolism is a fundamental process governing the ability of CD4+ helper T cells (TH) to polarize into different functional fates. Deficiency in ornithine decarboxylase, a crucial enzyme for polyamine synthesis, results in a severe failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across TH cell subsets. Polyamines control TH differentiation by providing substrates for deoxyhypusine synthase, which synthesizes the amino acid hypusine, and mice in which T cells are deficient for hypusine develop severe intestinal inflammatory disease. Polyamine-hypusine deficiency caused widespread epigenetic remodeling driven by alterations in histone acetylation and a re-wired tricarboxylic acid (TCA) cycle. Thus, polyamine metabolism is critical for maintaining the epigenome to focus TH cell subset fidelity.

Keywords: T cells; eIF5A; hypusine; immunity; immunometabolism; metabolism; polyamines

DOI: https://doi.org/10.1016/j.cell.2021.06.007