Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity

Swanson, Grace; Estill, Molly; Diamond, Michael P.; Legro, Richard S.; Coutifaris, Christos; Barnhart, Kurt T.; Huang, Hao; Hansen, Karl R.; Trussell, J. C.; Coward, R. Matthew; Zhang, Heping; Goodrich, Robert; Krawetz, Stephen A.

doi:10.1080/15592294.2019.1644880

Cited by 17 publications

(21 citation statements)

References 90 publications

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“…Several labs independently demonstrated that injecting total RNA isolated from sperm exposed to environmental manipulations, specific classes of sncRNA (often differentiated by size), or even specific environmentally-responsive sncRNA into newly fertilized zygotes was sufficient to www.nature.com/scientificreports/ transmit/phenocopy complex phenotypes in affected offspring 17,[19][20][21][22][23][24][25] . Epidemiological studies suggest that similar processes may link paternal adverse experiences and offspring disease risk, but causal or prospective data are lacking 28,39,42,[53][54][55][56] . Progress in the field has been held back by a lack of critical details regarding many of the necessary factors to design prospective clinical studies and test such hypotheses.…”

Section: Discussionmentioning

confidence: 99%

“…A growing number of human subject studies also demonstrated sperm sncRNA populations vary in association with diverse environmental exposures or experiences (e.g., smoking, diet, obesity, and stress/trauma) 28 , 39 , 42 , 53 – 58 . However, the majority of these studies were constrained to a single timepoint or to a single within-subject comparison.…”

Section: Introductionmentioning

confidence: 99%

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Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs

Morgan

Shetty

Chan

et al. 2020

Sci Rep

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Epidemiological studies from the last century have drawn strong associations between paternal life experiences and offspring health and disease outcomes. Recent studies have demonstrated sperm small non-coding RNA (sncRNA) populations vary in response to diverse paternal insults. However, for studies in retrospective or prospective human cohorts to identify changes in paternal germ cell epigenetics in association with offspring disease risk, a framework must first be built with insight into the expected biological variation inherent in human populations. In other words, how will we know what to look for if we don’t first know what is stable and what is dynamic, and what is consistent within and between men over time? From sperm samples from a ‘normative’ cohort of healthy human subjects collected repeatedly from each subject over 6 months, 17 healthy male participants met inclusion criteria and completed donations and psychological evaluations of perceived stress monthly. sncRNAs (including miRNA, piRNA, and tRNA) isolated from mature sperm from these samples were subjected to Illumina small RNA sequencing, aligned to subtype-specific reference transcriptomes, and quantified. The repeated measures design allowed us to define both within- and between-subject variation in the expression of 254 miRNA, 194 tRNA, and 937 piRNA in sperm over time. We developed screening criteria to identify a subset of potential environmentally responsive ‘dynamic’ sperm sncRNA. Implementing complex modeling of the relationships between individual dynamic sncRNA and perceived stress states in these data, we identified 5 miRNA (including let-7f-5p and miR-181a-5p) and 4 tRNA that are responsive to the dynamics of prior stress experience and fit our established mouse model. In the current study, we aligned repeated sampling of human sperm sncRNA expression data with concurrent measures of perceived stress as a novel framework that can now be applied across a range of studies focused on diverse environmental factors able to influence germ cell programming and potentially impact offspring development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs

Morgan

Shetty

Chan

et al. 2020

Sci Rep

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“…For expression in sperm, we downloaded the raw sequencing reads from 8 healthy individuals (Swanson et al, 2020). We pseudoaligned these reads to a fasta file containing all human cDNA sequences (Homo_sapiens.GRCh37.75.cdna.all.fa; downloaded from ENSEMBL), and subsequently quantified transcript abundances with Salmon (version 0.10.0) (Patro et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

Natural selection acts on epigenetic marks

Boukas

Björnsson

Hansen

2020

Preprint

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ABSTRACTA fundamental component of molecular evolution are the rules that govern when, and why, a given change (allele) is deleterious or neutral. The ability to define such rules for epialleles – analogous to the rules at the DNA sequence level – would thus have profound implications for our understanding of epigenetic variation and evolution. Here, we focus on promoter methylation in the male human germline, which – apart from its role in gene regulation – is also known to greatly increase the mutation rate of CpG dinucleotides. We first develop a simple but general approach for detecting selection on epialleles, which does not require populationscale data. We then show that germline promoter methylation is deleterious at loss-of-function intolerant genes, but neutral at loss-of-function tolerant ones. In concordance with this, a human-mouse comparative analysis of sperm methylomes reveals strong suppression of methylation acquisition at loss-of-function intolerant promoters. We demonstrate that this selection is neither a secondary consequence of germline gene expression levels, nor of promoter H3K4me3 levels. Rather, the deleteriousness of promoter methylation is explained by its mutagenic effect on the underlying CpGs. Our results thus address a long-standing open question in molecular evolution, providing the first demonstration of selection acting on an epigenetic mutation rate modifier to locally dictate the mutation rate in humans. They also suggest the existence of a mechanism that preferentially protects loss-of-function intolerant promoters from methylation in the germline. Finally, they directly refute the prevailing dogma that CpG islands are not under active selection.

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“…RNAs (RNA elements and messenger RNA) are found in the sperm head, nucleus, and residual cytoplasm of the sperm [73][74][75]. Sperm RNA is implicated in regulating the epigenetic code of the embryo [76]. There are no treatments currently available for defects in the RNAs that are reflective of disease, but it does provide a mechanistic understanding of the basis of infertility [77][78][79].…”

Section: Rna-sperm Transcriptsmentioning

confidence: 99%

Male Infertility is a Women’s Health Issue—Research and Clinical Evaluation of Male Infertility Is Needed

Turner

Rambhatla

Schon

et al. 2020

Cells

Self Cite

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Infertility is a devastating experience for both partners as they try to conceive. Historically, when a couple could not conceive, the woman has carried the stigma of infertility; however, men and women are just as likely to contribute to the couple's infertility. With the development of assisted reproductive technology (ART), the treatment burden for male and unexplained infertility has fallen mainly on women. Equalizing this burden requires reviving research on male infertility to both improve treatment options and enable natural conception. Despite many scientific efforts, infertility in men due to sperm dysfunction is mainly diagnosed by a semen analysis. The semen analysis is limited as it only examines general sperm properties such as concentration, motility, and morphology. A diagnosis of male infertility rarely includes an assessment of internal sperm components such as DNA, which is well documented to have an impact on infertility, or other components such as RNA and centrioles, which are beginning to be adopted. Assessment of these components is not typically included in current diagnostic testing because available treatments are limited. Recent research has expanded our understanding of sperm biology and suggests that these components may also contribute to the failure to achieve pregnancy. Understanding the sperm's internal components, and how they contribute to male infertility, would provide avenues for new therapies that are based on treating men directly for male infertility, which may enable less invasive treatments and even natural conception.

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Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity

Cited by 17 publications

References 90 publications

Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs

Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs

Natural selection acts on epigenetic marks

Male Infertility is a Women’s Health Issue—Research and Clinical Evaluation of Male Infertility Is Needed

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