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Multi-tissue transcriptional changes and core circadian clock disruption following intensive care

Objective: Both critical illness and current care have been hypothesized to upset daily rhythms and impair molecular circadian function. However, the influence of critical illness on clock function in different tissues and on circadian output genes are unknown. Here we evaluate the effect of critica...

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Autores principales: Hollis, Henry C., Francis, Julian N., Anafi, Ron C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9420996/
https://www.ncbi.nlm.nih.gov/pubmed/36045754
http://dx.doi.org/10.3389/fphys.2022.942704
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author Hollis, Henry C.
Francis, Julian N.
Anafi, Ron C.
author_facet Hollis, Henry C.
Francis, Julian N.
Anafi, Ron C.
author_sort Hollis, Henry C.
collection PubMed
description Objective: Both critical illness and current care have been hypothesized to upset daily rhythms and impair molecular circadian function. However, the influence of critical illness on clock function in different tissues and on circadian output genes are unknown. Here we evaluate the effect of critical care and illness on transcription, focusing on the functional organization of the core circadian oscillator. Methods: We downloaded RNAseq count data from the Genotype-Tissue Expression (GTEx) project. Treating mechanical ventilation as a marker for intensive care, we stratified samples into acute death (AD) and intensive care (IC) groups based on the documented Hardy Death Scale. We restricted our analysis to the 25 tissues with >50 samples in each group. Using the edgeR package and controlling for collection center, gender, and age, we identified transcripts differentially expressed between the AD and IC groups. Overrepresentation and enrichment methods were used to identify gene sets modulated by intensive care across tissues. For each tissue, we then calculated the delta clock correlation distance (ΔCCD), a comparative measure of the functional organization of the core circadian oscillator, in the both the AD and IC groups. The statistical significance of the ΔCCD was assessed by permutation, modifying a pre-existing R package to control for confounding variables. Results: Intensive care, as marked by ventilation, significantly modulated the expression of thousands of genes. Transcripts that were modulated in ≥75% of tissues were enriched for genes involved in mitochondrial energetics, cellular stress, metabolism, and notably circadian regulation. Transcripts that were more markedly affected, in ≥10 tissues, were enriched for inflammation, complement and immune pathways. Oscillator organization, as assessed by ΔCCD, was significantly reduced in the intensive care group in 11/25 tissues. Conclusion: Our findings support the hypothesis that patients in intensive care have impaired molecular circadian rhythms. Tissues involved in metabolism and energetics demonstrated the most marked changes in oscillator organization. In adipose tissue, there was a significant overlap between transcripts previously established to be modulated by sleep deprivation and fasting with those modulated by critical care. This work suggests that intensive care protocols that restore sleep/wake and nutritional rhythms may be of benefit.
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spelling pubmed-94209962022-08-30 Multi-tissue transcriptional changes and core circadian clock disruption following intensive care Hollis, Henry C. Francis, Julian N. Anafi, Ron C. Front Physiol Physiology Objective: Both critical illness and current care have been hypothesized to upset daily rhythms and impair molecular circadian function. However, the influence of critical illness on clock function in different tissues and on circadian output genes are unknown. Here we evaluate the effect of critical care and illness on transcription, focusing on the functional organization of the core circadian oscillator. Methods: We downloaded RNAseq count data from the Genotype-Tissue Expression (GTEx) project. Treating mechanical ventilation as a marker for intensive care, we stratified samples into acute death (AD) and intensive care (IC) groups based on the documented Hardy Death Scale. We restricted our analysis to the 25 tissues with >50 samples in each group. Using the edgeR package and controlling for collection center, gender, and age, we identified transcripts differentially expressed between the AD and IC groups. Overrepresentation and enrichment methods were used to identify gene sets modulated by intensive care across tissues. For each tissue, we then calculated the delta clock correlation distance (ΔCCD), a comparative measure of the functional organization of the core circadian oscillator, in the both the AD and IC groups. The statistical significance of the ΔCCD was assessed by permutation, modifying a pre-existing R package to control for confounding variables. Results: Intensive care, as marked by ventilation, significantly modulated the expression of thousands of genes. Transcripts that were modulated in ≥75% of tissues were enriched for genes involved in mitochondrial energetics, cellular stress, metabolism, and notably circadian regulation. Transcripts that were more markedly affected, in ≥10 tissues, were enriched for inflammation, complement and immune pathways. Oscillator organization, as assessed by ΔCCD, was significantly reduced in the intensive care group in 11/25 tissues. Conclusion: Our findings support the hypothesis that patients in intensive care have impaired molecular circadian rhythms. Tissues involved in metabolism and energetics demonstrated the most marked changes in oscillator organization. In adipose tissue, there was a significant overlap between transcripts previously established to be modulated by sleep deprivation and fasting with those modulated by critical care. This work suggests that intensive care protocols that restore sleep/wake and nutritional rhythms may be of benefit. Frontiers Media S.A. 2022-08-15 /pmc/articles/PMC9420996/ /pubmed/36045754 http://dx.doi.org/10.3389/fphys.2022.942704 Text en Copyright © 2022 Hollis, Francis and Anafi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Hollis, Henry C.
Francis, Julian N.
Anafi, Ron C.
Multi-tissue transcriptional changes and core circadian clock disruption following intensive care
title Multi-tissue transcriptional changes and core circadian clock disruption following intensive care
title_full Multi-tissue transcriptional changes and core circadian clock disruption following intensive care
title_fullStr Multi-tissue transcriptional changes and core circadian clock disruption following intensive care
title_full_unstemmed Multi-tissue transcriptional changes and core circadian clock disruption following intensive care
title_short Multi-tissue transcriptional changes and core circadian clock disruption following intensive care
title_sort multi-tissue transcriptional changes and core circadian clock disruption following intensive care
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9420996/
https://www.ncbi.nlm.nih.gov/pubmed/36045754
http://dx.doi.org/10.3389/fphys.2022.942704
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