Hypoxia induces transgenerational epigenetic inheritance of small RNAs

Wang, Simon Yuan; Kim, Kathleen; O’Brown, Zach Klapholz; Levan, Aileen; Dodson, Anne E.; Kennedy, Scott; Chernoff, Chaim; Greer, Eric Lieberman

doi:10.1016/j.celrep.2022.111800

Cited by 14 publications

(7 citation statements)

References 93 publications

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“…Such contradictory results are difficult to explain since such responses are dependent on the level of hypoxia, its duration and the stage at which the stress was applied. Importantly, since this experiment suggests epigenetic factors play a crucial role in the cellular response to hypoxia [25][26][27], the study of the critical window that we discovered here is especially important because of the likely involvement of nongenetic factors in otherwise hypoxia-tolerant HA flies. In addition, our results suggest that the hypoxia sensitivity experienced during the critical time window predisposes them to conditions later in life.…”

Section: Discussionmentioning

confidence: 87%

The Pupa Stage Is the Most Sensitive to Hypoxia in Drosophila melanogaster

Stobdan,

Wen,

Lu-Bo

et al. 2024

IJMS

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Hypoxia not only plays a critical role in multiple disease conditions; it also influences the growth and development of cells, tissues and organs. To identify novel hypoxia-related mechanisms involved in cell and tissue growth, studying a precise hypoxia-sensitive time window can be an effective approach. Drosophila melanogaster has been a useful model organism for studying a variety of conditions, and we focused in this study on the life cycle stages of Drosophila to investigate their hypoxia sensitivity. When normoxia-grown flies were treated with 4% O2 at the pupa stage for 3, 2 and 1 day/s, the eclosion rates were 6.1%, 66.7% and 96.4%, respectively, and, when 4% O2 was kept for the whole pupa stage, this regimen was lethal. Surprisingly, when our hypoxia-adapted flies who normally live in 4% O2 were treated with 4% O2 at the pupa stage, no fly eclosed. Within the pupa stage, the pupae at 2 and 3 days after pupae formation (APF), when treated for 2 days, demonstrated 12.5 ± 8.5% and 23.6 ± 1.6% eclosion, respectively, but this was completely lethal when treated for 3 days. We conclude that pupae, at 2 days APF and for a duration of a minimum of 2 days, were the most sensitive to hypoxia. Our data from our hypoxia-adapted flies clearly indicate that epigenetic factors play a critical role in pupa-stage hypoxia sensitivity.

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Section: Discussionmentioning

confidence: 87%

The Pupa Stage Is the Most Sensitive to Hypoxia in Drosophila melanogaster

Stobdan,

Wen,

Lu-Bo

et al. 2024

IJMS

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“…Moreover, the males’ sperm outnumbers and outperforms the hermaphroditic sperm, so cross fertilization becomes advantageous as it ensures a wider distribution of the adverse information among the descendants. Indeed, following mating, the sperm contributes to the 1-cell embryo a significant amount of RNAs, particularly of endogenous siRNAs and piRNAs 68 , 69 , 79 . Interestingly, siRNAs may trans-generationally enhance mating chances, and by this, spread the epigenetic information 80 .…”

Section: Discussionmentioning

confidence: 99%

Inheritance of associative memories and acquired cellular changes in C. elegans

et al. 2023

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Experiences have been shown to modulate behavior and physiology of future generations in some contexts, but there is limited evidence for inheritance of associative memory in different species. Here, we trained C. elegans nematodes to associate an attractive odorant with stressful starvation conditions and revealed that this associative memory was transmitted to the F1 progeny who showed odor-evoked avoidance behavior. Moreover, the F1 and the F2 descendants of trained animals exhibited odor-evoked cellular stress responses, manifested by the translocation of DAF-16/FOXO to cells’ nuclei. Sperm, but not oocytes, transmitted these odor-evoked cellular stress responses which involved H3K9 and H3K36 methylations, the small RNA pathway machinery, and intact neuropeptide secretion. Activation of a single chemosensory neuron sufficed to induce a serotonin-mediated systemic stress response in both the parental trained generation and in its progeny. Moreover, inheritance of the cellular stress responses increased survival chances of the progeny as exposure to the training odorant allowed the animals to prepare in advance for an impending adversity. These findings suggest that in C. elegans associative memories and cellular changes may be transferred across generations.

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“…Furthermore, as exposure to limiting oxygen or nutrients has been reported to have transgenerational effects on descendants’ metabolic programming, behavior, and fecundity in C . elegans [ 70 – 72 ], exploring the role of PQM-1 in these processes may shed light on the physiological role of negative regulation of hypoxic survival.…”

Section: Discussionmentioning

confidence: 99%

ADAR-mediated regulation of PQM-1 expression in neurons impacts gene expression throughout C. elegans and regulates survival from hypoxia

Mahapatra,

Dhakal,

Noguchi

et al. 2023

PLoS Biol

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The ability to alter gene expression programs in response to changes in environmental conditions is central to the ability of an organism to thrive. For most organisms, the nervous system serves as the master regulator in communicating information about the animal’s surroundings to other tissues. The information relay centers on signaling pathways that cue transcription factors in a given cell type to execute a specific gene expression program, but also provide a means to signal between tissues. The transcription factor PQM-1 is an important mediator of the insulin signaling pathway contributing to longevity and the stress response as well as impacting survival from hypoxia. Herein, we reveal a novel mechanism for regulating PQM-1 expression specifically in neural cells of larval animals. Our studies reveal that the RNA-binding protein (RBP), ADR-1, binds to pqm-1 mRNA in neural cells. This binding is regulated by the presence of a second RBP, ADR-2, which when absent leads to reduced expression of both pqm-1 and downstream PQM-1 activated genes. Interestingly, we find that neural pqm-1 expression is sufficient to impact gene expression throughout the animal and affect survival from hypoxia, phenotypes that we also observe in adr mutant animals. Together, these studies reveal an important posttranscriptional gene regulatory mechanism in Caenorhabditis elegans that allows the nervous system to sense and respond to environmental conditions to promote organismal survival from hypoxia.

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Hypoxia induces transgenerational epigenetic inheritance of small RNAs

Cited by 14 publications

References 93 publications

The Pupa Stage Is the Most Sensitive to Hypoxia in Drosophila melanogaster

The Pupa Stage Is the Most Sensitive to Hypoxia in Drosophila melanogaster

Inheritance of associative memories and acquired cellular changes in C. elegans

ADAR-mediated regulation of PQM-1 expression in neurons impacts gene expression throughout C. elegans and regulates survival from hypoxia

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