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Developmentally dynamic chromatin state at loci regulating interorgan communication

ABSTRACT: Interorgan communication, metabolite regulation and drug handling all require fine-tuned transport of small molecules across cellular membranes. Approximately 1000 protein-coding genes – including hundreds of solute carrier (SLC) and ATP-binding cassette (ABC) transporters as well as enzymes and transcription factors-mediate small molecule organ crosstalk via a process known as “remote sensing and signaling (RSS)”. The RSS protein coding genes greatly overlap with those regulating absorption, digestion, metabolism and excretion (ADME) of small molecule drugs. However, it is not known how chromatin and epigenetic state at these loci are coordinately regulated during the development of the liver and kidney, which control the small molecule composition of the blood, or the brain, whose physiology relies upon proper regulation of this process. Understanding how epigenetic state changes during development at these loci provides insight into how the body attains autonomous functionality.

ORGANISM(S): Mus musculus

PROVIDER: GSE295997 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:The effects of fasting have been studied extensively, predominantly on isolated processes, within a specific organ. No comprehensive study of the adaptations was available for different organs, let alone interrelating them, which left the understanding of the body’s orchestration of fasting response limited. The gene expression profiles of brain, small intestine, kidney, liver and skeletal muscle were therefore studied in mice subjected to short, moderate and prolonged fasting. Functional category enrichment, network, and text-mining analyses were employed to scrutinize the overall adaptive response, aiming to identify responsive pathways, processes and networks, and their regulation. The implicated processes did not follow the accepted carbohydrate-lipid-protein succession of energy substrates expenditure. Instead, they were activated simultaneously in different organs during the whole duration of fasting. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney, which showed biochemically similar, orchestrated responses. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, tied in with increased proteolysis in the muscle. Enhanced defence against oxidative damage, obvious in all the organs, was the top reaction of the brain, otherwise shown to be extremely well protected from starvation. The major transcription regulators of fasting response in different organs were FoxO transcription factors, AP-1, p53, cMyc, Sp1, EGF and HNF4α. The revealed interorgan interactions between metabolic, inflammatory and cell turnover responses are essential when designing strategies to treat the starvation affected individuals, while stressing the significance of using complimentary bioinformatics tools in the high-throughput data analysis. 6 week-old male FVB mice were fasted for 0, 12, 24, 48 or 72 hours before sacrifice (N = 5 per group). From each mouse total RNA was isolated from five organs - liver, small intestine, kidney, brain, and calf muscle. Five microarrays per experimental condition (five tissues, five timepoints) were performed. We used a common reference design. The single common-reference sample was a pool of equal amounts of RNA from all the samples investigated, including additional samples from 5 mice that were fasted for 48 hours and supplemented with vitamin B complex after 24 and 36 hours of fasting.

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Developmentally dynamic chromatin state at loci regulating interorgan communication

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