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Male Obesity Impacts DNA Methylation Reprogramming in Sperm

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Male Obesity Impacts DNA Methylation Reprogramming in Sperm Keyhan et al. Clin Epigenet (2021) 13:17 https://doi.org/10.1186/s13148-020-00997-0 RESEARCH Open Access Male obesity impacts DNA methylation reprogramming in sperm Sanaz Keyhan1, Emily Burke2, Rose Schrott3,4, Zhiqing Huang3, Carole Grenier3, Thomas Price1, Doug Raburn1, David L. Corcoran5, Adelheid Soubry6, Catherine Hoyo7 and Susan K. Murphy3,4* Abstract Background: Male obesity has profound efects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse efects of male obesity to be passed to the next gen- eration. DNA methylation contributes to gene regulation and is erased and re-established during gametogenesis. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental infuences, including the obesogenic environment, that could disrupt reprogramming fdelity. Here we conducted an exploratory analysis that showed that overweight/obesity (n 20) is associated with diferences in mature spermatozoa DNA methylation profles relative to controls with nor- mal= BMI (n 47). = Results: We identifed 3264 CpG sites in human sperm that are signifcantly associated with BMI (p < 0.05) using Infn- ium HumanMethylation450 BeadChips. These CpG sites were signifcantly overrepresented among genes involved in transcriptional regulation and misregulation in cancer, nervous system development, and stem cell pluripotency. Analysis of individual sperm using bisulfte sequencing of cloned alleles revealed that the methylation diferences are present in a subset of sperm rather than being randomly distributed across all sperm. Conclusions: Male obesity is associated with altered sperm DNA methylation profles that appear to afect repro- gramming fdelity in a subset of sperm, suggestive of an infuence on the spermatogonia. Further work is required to determine the potential heritability of these DNA methylation alterations. If heritable, these changes have the poten- tial to impede normal development. Keywords: Epigenetics, Methylation, Reprogramming, Sperm, Obesity, TIEGER study Background changes in DNA methylation [1]. Te patterns of DNA A growing body of evidence supports that early-life methylation throughout the genome (referred to as the environmental exposures can increase the risk of adult methylome) help to regulate temporal and spatial gene chronic disease. Efects of environmental exposures expression. Plasticity of the methylome lends itself to may be mediated through epigenetic changes, including heightened vulnerability to potential detrimental errors during periods of epigenetic fux, especially during the methylation reprogramming events that take place *Correspondence: [email protected] immediately post-fertilization and during gametogenesis 3 Division of Reproductive Sciences, Department of Obstetrics [2]. and Gynecology, Duke University Medical Center, 501 W. Main Street, Suite 510, The Chestefeld Building, PO Box 90534, Durham, NC 27701, After puberty, sperm production is continuous USA throughout adult life. Tis requires that sperm-specifc Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Keyhan et al. Clin Epigenet (2021) 13:17 Page 2 of 14 DNA methylation profles established during repro- Table 1 Study participant table gramming of the primordial germ cells are maintained Normal Overweight/ p** in the maturing sperm cells, and fnal methylation pat- weight obese n 47* n 20* terns must be established. Te DNA methyltransferase = = enzymes are present throughout spermatogenesis, and n % n % studies in rodents have shown that de novo DNA meth- Age 0.0033 ylation is continued even after the spermatids transit 18–24 26 55.3 3 15.0 into the epididymis for maturation [3, 4]. As a result of 25–29 12 25.5 6 30.0 this continual need for methylation maintenance and 30–37 9 19.1 11 55.0 completion of reprogramming, DNA methylation in Highest degree of education 0.97 male gametes may be more vulnerable to exogenous and High school 6 12.8 1 5.0 endogenous environmental infuences, including an obe- Some college or college degree 28 59.6 13 65.0 sogenic environment [5–11]. Graduate 12 25.5 6 30.0 We previously demonstrated that babies born to obese Marital status 0.0070 fathers have altered DNA methylation at several regula- Single 31 65.9 6 30.0 tory regions of imprinted genes [10, 11]. Imprinted genes Married/living with partner 16 34.0 14 70.0 are defned by DNA methylation that is divergent at the Biologically fathered children 0.30 same genomic locations in sperm versus oocytes. Tese No 42 89.4 16 80.0 imprinted regions are diferentially established after sex Yes 5 10.6 4 20.0 determination in the embryo during gametogenesis and Sperm concentration 0.78 give rise to monoallelic gene expression. Here, the active < 15 106/ml 3 6.4 1 5.0 and silenced alleles in each somatic cell are determined × 15 106/ml 41 87.2 19 95.0 by the epigenetic marks that distinguish the two paren- ≥ × Sperm motility 0.39 tal copies. Te ~ 100 known imprinted genes are critical < 40% 7 14.9 5 25.0 mediators of early growth and development, yet they 40% 37 78.7 15 75.0 comprise a relatively small subset of the genes through- ≥ out the genome. A follow-up study sought to understand Patient at fertility clinic 0.0007 these methylation changes at imprinted regions by ana- No 40 85.1 9 45.0 lyzing methylation patterns in mature spermatozoa and Yes 7 14.9 11 55.0 semen parameters of normal weight men versus men who Bolded values were deemed signifcant with p < 0.05 * were overweight or obese [12]. We reported signifcantly Sums less than the total reported n indicate missing data; percentage was calculated on known data altered DNA methylation in sperm of the overweight ** p-values calculated using Chi-squared tests and obese men as compared to the normal weight men at multiple imprinted gene regulatory regions. Herein we greatly expand our initial studies by conducting an BMI categories had not previously biologically fathered exploratory examination of the infuence of overweight/ children. Using the Kendall’s rank correlation, we found obesity on DNA methylation throughout the genome. no signifcant relationships between any of the semen parameters analyzed and BMI of all study subjects, nor Results when study subjects were stratifed by BMI (overweight/ Study subjects obese or normal). Study subject characteristics by BMI category are pre- sented in Table 1. Twenty of the 67 men were categorized as overweight/obese (BMI > 25), representing 29.9% of Altered DNA methylation in sperm from men with elevated our study population. One man was excluded from the BMI study because of a BMI of 59 kg/m2, and one man was Te Illumina Infnium HumanMethylation450 BeadChip excluded due to insufcient sample availability. Tere (hereafter, 450K) is designed to generate quantitative was no signifcant diference between BMI categories DNA methylation data for 485,512 CpG sites through- in education, biological paternity, sperm concentration, out the genome. In order to account for the two difer- or sperm motility. Tere were signifcant diferences ent probe design types on the 450K BeadChip, the CpG between BMI categories for age, marital status, and being sites were subjected to subset quantile within-array a patient at the Duke Fertility Center, with overweight/ normalization (SWAN). Dropping CpG probes with obese men being older, more likely to be married, and poor detection p-values resulted in retention of 485,498 more likely to be patients. Te majority of men in both probes. All unreliable probes based on prior criteria [13] Keyhan et al. Clin Epigenet (2021) 13:17 Page 3 of 14 were removed, reducing the number of retained probes 2–19). Te top two genes with multiple afected CpGs to 294,833. Finally, probes that were invariant across all were Protein Tyrosine Phosphatase Receptor Type N2 –5 samples (β variance < 2 × 10 ) were discarded, resulting (PTPRN2; 19 sites with methylation values ranging in a total of 291,061 retained CpG sites for analysis [14, from 3.4% lower to 3.6% higher in healthy versus over- 15, 17]. weight/obese; unadjusted p values ranging from 2.4e−5 Linear regression analysis was conducted on the to 0.007) and zinc fnger protein 33A (ZNF33A; 10 sites 291,061 CpG sites controlling for age, race, smok- with methylation values ranging from 1.3% to 6.4% ing status and clinic patient status. A higher BMI was lower in healthy versus overweight/obese men; unad- associated with one CpG site, cg24769403, which justed p values ranging from 0.0001 to 0.008). passed signifcance at the false discovery rate (FDR To determine whether there were functionally related p = 0.007; 9.9% higher methylation in overweight/obese groups of genes that were targeted by BMI-associated men) and the more conservative Bonferroni correc- alterations in sperm DNA methylation, we entered the tion (p 1.0 10–7; Fig.
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