Cross-tolerance: embryonic heat conditioning induces inflammatory resilience by affecting different layers of epigenetic mechanisms regulating <i>IL6</i> expression later in life

Rosenberg, Tali; Kisliouk, Tatiana; Ben-Nun, Osher; Cramer, Tomer; Meiri, Noam

doi:10.1080/15592294.2020.1795596

Cited by 7 publications

(28 citation statements)

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“…This finding corroborates with our previous results, showing that embryonic heat conditioning induces transcriptional changes in the hypothalamus that, in turn, contribute to thermal and immunological crosstolerance phenotypes later in life. 3,4 More importantly, our results (Figure 1) support the fact that EHC induces transgenerational effects on thermal and immunological resilience traits.…”

Section: Ehc Induces Thermal and Immunological Resilience In Noncondi...supporting

confidence: 77%

“…Ten days posthatch, the chicks' body temperature was measured 6 h into either heat or lipopolysaccharide (LPS) challenge, as previously reported (Figure 1A). 4 Although they had not been treated, we found that F 1 offspring of male/female EHC parents crossed with female/male CTRL parents, respectively, or of both EHC parents, presented reduced body temperature during either heat or LPS challenge (Figure 1B,C). Heat challenge revealed significant paternal and maternal effects ( F (1,36) = 129, p < .0001; F (1,36) = 61, p < .001, respectively), along with a significant interaction between them ( F (1,36) = 268, p < .0001; Figure 1B).…”

Section: Resultsmentioning

confidence: 81%

“…As the distribution was normal, the parameters were not transformed. There was no sample size calculation; the sample size was determined on the basis of previous studies 3,4 . Sample number ( n ) included the number of individual chicks in each treatment group (indicated in the figure legends).…”

Section: Methodsmentioning

confidence: 99%

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Embryonic heat conditioning in chicks induces transgenerational heat/immunological resilience via methylation on regulatory elements

et al. 2022

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The question of whether behavioral traits are heritable is under debate. An obstacle in demonstrating transgenerational inheritance in mammals originates from the maternal environment's effect on offspring phenotype. Here, we used in ovo embryonic heat conditioning (EHC) of first-generation chicks, demonstrating heredity of both heat and immunological resilience, confirmed by a reduced fibril response in their untreated offspring to either heat or LPS challenge. Concordantly, transcriptome analysis confirmed that EHC induces changes in gene expression in the anterior preoptic hypothalamus (APH) that contribute to these phenotypes in the offspring.To study the association between epigenetic mechanisms and trait heritability, DNAmethylation patterns in the APH of offspring of control versus EHC fathers were evaluated. Genome-wide analysis revealed thousands of differentially methylated sites (DMSs), which were highly enriched in enhancers and CCCTC-binding factor (CTCF) sites. Overlap analysis revealed 110 differentially expressed genes that were associated with altered methylation, predominantly on enhancers. Gene-ontology analysis shows pathways associated with immune response, chaperone-mediated protein folding, and stress response. For the proof of concept, we focused on HSP25 and SOCS3, modulators of heat and immune responses, respectively. Chromosome conformational capture (3C) assay identified interactions between their promoters and methylated enhancers, with the strongest frequency on CTCF binding sites.Furthermore, gene expression corresponded with the differential methylation patterns, and presented increased CTCF binding in both hyper-and hypomethylated DMSs. Collectively, we demonstrate that EHC induces transgenerational thermalThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Section: Ehc Induces Thermal and Immunological Resilience In Noncondi...supporting

confidence: 77%

Section: Resultsmentioning

confidence: 81%

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Embryonic heat conditioning in chicks induces transgenerational heat/immunological resilience via methylation on regulatory elements

et al. 2022

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“…Over several days of recovery from heat stroke, in mice, corticosterone concentrations are elevated, suggesting a persistent and systemic exposure to increased glucocorticoids that might reprogram the epigenome (Murray, Brant et al., 2021). Previous studies in chicks indicate that embryonic heat stress produces an epigenetically mediated cross‐tolerance effect on interleukin‐6 secretion in response to in vivo LPS (repressive DNA methylation and histone marks on intron 1 of the interleukin‐6 gene) (Rosenberg et al., 2021). This finding supports glucocorticoid‐induced effects of heat stress on long‐term immune responsiveness (Rosenberg et al., 2021).…”

Section: Long‐term Disease Risk After Heat Stroke Exposure: a Case Fo...mentioning

confidence: 99%

“…Previous studies in chicks indicate that embryonic heat stress produces an epigenetically mediated cross‐tolerance effect on interleukin‐6 secretion in response to in vivo LPS (repressive DNA methylation and histone marks on intron 1 of the interleukin‐6 gene) (Rosenberg et al., 2021). This finding supports glucocorticoid‐induced effects of heat stress on long‐term immune responsiveness (Rosenberg et al., 2021).…”

Section: Long‐term Disease Risk After Heat Stroke Exposure: a Case Fo...mentioning

confidence: 99%

Epigenetic responses to heat: From adaptation to maladaptation

Murray

Clanton

Horowitz

2022

Experimental Physiology

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New Findings What is the topic of this review?This review outlines the history of research on epigenetic adaptations to heat exposure. The perspective taken is that adaptations reflect properties of hormesis, whereby low, repeated doses of heat induce adaptation (acclimation/acclimatization); whereas brief, life‐threatening exposures can induce maladaptive responses. What advances does it highlight?The epigenetic mechanisms underlying acclimation/acclimatization comprise specific molecular programmes on histones that regulate heat shock proteins transcriptionally and protect the organism from subsequent heat exposures, even after long delays. The epigenetic signalling underlying maladaptive responses might rely, in part, on extensive changes in DNA methylation that are sustained over time and might contribute to later health challenges. Abstract Epigenetics plays a strong role in molecular adaptations to heat by producing a molecular memory of past environmental exposures. Moderate heat, over long periods of time, induces an ‘adaptive’ epigenetic memory, resulting in a condition of ‘resilience’ to future heat exposures or cross‐tolerance to other forms of toxic stress. In contrast, intense, life‐threatening heat exposures, such as severe heat stroke, can result in a ‘maladaptive’ epigenetic memory that can place an organism at risk of later health complications. These cellular memories are coded by post‐translational modifications of histones on the nucleosomes and/or by changes in DNA methylation. They operate by inducing changes in the level of gene transcription and therefore phenotype. The adaptive response to heat acclimation functions, in part, by facilitating transcription of essential heat shock proteins and exhibits a biphasic short programme (maintaining DNA integrity, followed by a long‐term consolidation). The latter accelerates acclimation responses after de‐acclimation. Although less studied, the maladaptive responses to heat stroke appear to be coded in long‐lasting changes in DNA methylation near the promoter region of genes involved with basic cell function. Whether these memories are also encoded in histone modifications is not yet known. There is considerable evidence that both adaptive and maladaptive epigenetic responses to heat can be inherited, although most evidence comes from lower organisms. Future challenges include understanding the signalling mechanisms responsible and discovering new ways to promote adaptive responses while suppressing maladaptive responses to heat, as all life forms adapt to life on a warming planet.

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Early‐life thermal stress mediates long‐term alterations in hypothalamic microglia

Ben-Nun

Kisliouk

Marco

et al. 2021

Glia

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Stressful environmental events in early life have long-lasting consequences on later stress responses. We previously showed that heat conditioning of 3-day-old chicks during the critical period of heat-response development leads to heat vulnerability later in life. Here we assessed the role of early-life heat stress on the inflammatory response in the chick anterior hypothalamus (AH), focusing on hypothalamic microglia. We identified the microglial cell population in the chick AH using anti-KUL01 and anti-CD45 antibodies. Specific microglial features were also confirmed by expression of their signature genes. Under normal environmental conditions, hypothalamic microglia isolated from lipopolysaccharide (LPS)-injected chicks displayed a classical activated proinflammatory profile accompanied by a decreased homeostatic signature, demonstrating similarity of immune response with mammalian microglial cells. In accordance with our previous observations, conditioning of 3-dayold chicks under high ambient temperature decreased the number of newborn cells in the AH, among them microglial precursors. Although heat exposure did not affect microglial cell viability, it had a long-term impact on LPS-induced inflammatory response. Exposure to harsh heat led to heat vulnerability, and attenuated recruitment of peripheral monocytes and T cells into the AH following LPS challenge. Moreover, heat conditioning altered microglial reactivity, manifested as suppressed microglial activation in response to LPS. Innate immune memory developed by heat conditioning might underlie suppression of the microglial response to LPS challenge.We describe alterations in genome-wide CpG methylation profile of hypothalamic microglia, demonstrating probable epigenetic involvement in the reprogramming of microglial function, leading to heat-induced inflammatory cross-tolerance.

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Cross-tolerance: embryonic heat conditioning induces inflammatory resilience by affecting different layers of epigenetic mechanisms regulating IL6 expression later in life

Cited by 7 publications

References 73 publications

Embryonic heat conditioning in chicks induces transgenerational heat/immunological resilience via methylation on regulatory elements

Embryonic heat conditioning in chicks induces transgenerational heat/immunological resilience via methylation on regulatory elements

Epigenetic responses to heat: From adaptation to maladaptation

Early‐life thermal stress mediates long‐term alterations in hypothalamic microglia

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