\"Posttranslational histone modifications, DNA methylation patterns, and populat
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Question
"Posttranslational histone modifications, DNA methylation patterns, and populations of small noncoding RNAs in sperm have been implicated in the transgenerational transmission of paternal experience, with changes in these epigenetic marks observed following male exposure to such diverse stimuli as stress, malnutrition, and drugs of abuse. In particular, the role of sperm RNA as a mechanistic link between paternal experience and its consequences on offspring behavior and physiology has been emphasized by recent studies that characterize offspring phenotypes following in vitro fertilization and/or the experimental manipulation of total sperm RNA content. In our model of paternal stress, a reduced HPA (Hypothalamic-Pituitary-Adrenal) axis response in offspring was associated with the increased expression of nine miRs (miR-29c, miR-30a, miR-30c, miR-32, miR-193-5p, miR-204, miR-375, miR-5323p, and miR-698) in paternal sperm following chronic stress exposure. In the current study, to confirm causality of these miR changes in offspring neurodevelopmental programming, the nine miRs (multi-miR injection) were microinjected into single-cell zygotes. Two components were critical to control for in these experiments to ensure outcomes were clearly interpreted: (i) the injection process itself, and (ii) the increased overall miR concentration, which could overwhelm and inhibit the endogenous activity of the zygote RNA-induced silencing complex (RISC). Therefore, control injection conditions included a PBS injection to control for the zygote injection process itself, and a single-miR injection (randomly selected from one of the nine used in the composite) at the same overall concentration to control for miR concentration effects.
Remarkably, and important for our understanding of paternal RNA involvement in postfertilization development, the multi-miR injection produced a phenotype nearly identical to that of our paternal stress model, where both male and female mice from the multi-miR injections mounted a significantly blunted corticosterone response to an acute restraint stress as adults. A striking overlap was observed in the magnitude of effect on corticosterone production and its rate of rise and of recovery between multi-miR–injected animals and our previously reported paternal stress offspring (as shown in the schematic in Fig. 1F, below). The corticosterone response curve elicited by an acute stressor is multifaceted, with aspects of the curve (e.g., baseline, maximal rise, and rates of rise and recovery) regulated by specific brain regions, including the PVN, thalamus, and hippocampus. Thus, parallels in the shape of the corticosterone curves between this study and our paternal stress model emphasize similarities in programming mechanisms elicited by paternal sperm miRs. The single-miR injection did not affect the HPA axis corticosterone levels, suggesting that the specific and combinatorial activity of these sperm miRs alters stress axis responsivity. Certainly, as we did not examine each miR independently or in all possible combinations to determine the minimal complement necessary to produce the effect, future studies will need to examine the contribution of each of the nine miRs." (From: Rodgers et al. (2015) PNAS 112:13699: https://doi.org/10.1073/pnas.1508347112)
Based on this passage, which of the following statements are true or justified? Select ALL that apply for credit.
1. Injection with miR-193-5p alone led to a reduction in stress as measured by corticosterone levels
2.This work provides evidence that small RNAs that mitigate against stress are provided by the the egg cell post-fertilization
3. This study provides evidence that miRNAs can modify gene expression in male sperm cell that leads to offspring that do not handle stress well
4.Multiple miRNAs in sperm may contribute to offspring that exhibit similar corticosterone responses as offspring from dads that have been stressed out.
5.The epigentic state of female gametes is not involved in the paternal transmission of stress
6.Fathers that experience stress may lead to the expression of miRNAs in sperm that alters the response to stress of offspring
Explanation / Answer
In this communciation, the author have described a conneciton between sperm RNA and the behavioural and physiological changes of the offspring. The changes in the offspirng behaviour is studied after invitro fertilization. They havea model system where they have found that offsprings which are generated are showing a a reduced HPA (Hypothalamic-Pituitary-Adrenal) axis in response to stress. This reduction is associated with increase of nine miRNAs in paternal sperm. Alternatively we can say that when the father is experienceing a stree, his sperm is showing increased miRNA expression ( here 9 has been observed), which inturn loweirng the activity of HPA axis which is required in the time of stress. Following this they wants to see whether paternal RNA can influence the offspring behaviour or if expression of this miRNAs can have an effect on neurodevelopment of the offspring so they are showing this changed stress response. To check this they have injected those nine micro- RNAs in the zygote when int in single cell stage. At this experiment they have found the offsprings generated from this zygote are showing the same results as the offsprings which are generated from the stressed father/ parents.
5.The epigentic state of female gametes is not involved in the paternal transmission of stress
6.Fathers that experience stress may lead to the expression of miRNAs in sperm that alters the response to stress of offspring.
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