DNA methylation levels of imprinted and nonimprinted genes DMRs associated with defective human spermatozoa

Xu, Jinhua; Zhang, A; Zhang, Z; Wang, P; Qian, Yong; Shi, Huijuan; Xing, Qinghe; Du, Jing

doi:10.1111/and.12535

Cited by 41 publications

(36 citation statements)

References 31 publications

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“…In conclusion, DNA methylation has been closely associated with male infertility (66,121). Understanding the mechanisms underlying DNA methylation is particularly important in order to develop therapeutic strategies for male genital system diseases caused by abnormal sperm DNA methylation.…”

Section: Resultsmentioning

confidence: 97%

DNA methylation in spermatogenesis and male infertility

Cui¹,

Xuan

Wu³

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Infertility is a significant problem for human reproduction, with males and females equally affected. However, the molecular mechanisms underlying male infertility remain unclear. Spermatogenesis is a highly complex process involving mitotic cell division, meiosis cell division and spermiogenesis; during this period, unique and extensive chromatin and epigenetic modifications occur to bring about specific epigenetic profiles in spermatozoa. It has recently been suggested that the dysregulation of epigenetic modifications, in particular the methylation of sperm genomic DNA, may serve an important role in the development of numerous diseases. The present study is a comprehensive review on the topic of male infertility, aiming to elucidate the association between sperm genomic DNA methylation and poor semen quality in male infertility. In addition, the current status of the genetic and epigenetic determinants of spermatogenesis in humans is discussed. Contents1. Introduction 2. DNA methylation 3. DNA methylation and spermatogenesis 4. DNA methylation and genomic imprinting 5. DNA methylation and male infertility 6. Conclusion IntroductionEpigenetics is the study of genomic structural modifications that affect gene expression without altering the underlying nucleotide sequence (1-3). Epigenetic mechanisms involved in the regulation of gene expression include the regulation of non-coding RNA, chromatin remodeling, DNA methylation and histone modifications (4,5). Of these mechanisms, DNA methylation has been implicated in numerous biological functions, such as the development of spermatozoa and early embryos, and the repression of endogenous retrotransposons, while it also has a wide range of effects in gene expression (2,3,6). The dysregulation of DNA methylation has previously been associated with various human disorders, and has been shown to increase the risk of fertilization failure, dysfunction in embryogenesis, perinatal mortality, congenital abnormalities, preterm birth and low birth weight (7-11). The present review assesses the significance of DNA methylation in spermatogenesis in order to elucidate the association between the dysregulation of DNA methylation and male infertility. This may provide a basis for the prevention and treatment of male infertility, as well as permit the evaluation of the epigenetic quality of sperm in order to reduce the risk of epigenetic diseases in cases where conception is performed by assisted reproductive technology (ART). DNA methylationEpigenetic mechanisms are critical regulators of gene expression during spermatogenesis that may influence male fertility (12-14). Cytosine, a key DNA base, is methylated at the position, typically in the context of CpG dinucleotides. The methylation of constitutive heterochromatic and promoter regions is generally associated with reduced gene transcription (Fig. 1A) (15-18). Therefore, DNA methylation is a type of epigenetic modification that can effectively promote gene silencing (Fig. 1B). The methyl group for this chemical modif...

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Section: Resultsmentioning

confidence: 97%

DNA methylation in spermatogenesis and male infertility

Cui¹,

Xuan

Wu³

et al. 2016

Experimental and Therapeutic Medicine

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“…With ICSI, individual sperm are then selected visually based on motility and morphology by a trained embryologist for injection to an egg 7, 8. However, other important sperm attributes that can affect ART outcomes, including sperm DNA–chromatin or chromosomal integrity, mutational, or methylome composition, and the presence of reactive oxygen species (ROS)9, 10, 11, 12, 13, 14, 15, 16, 17 are typically not considered. In particular, long periods of incubation, as well as shear stresses due to centrifugation, increase ROS accumulation.…”

Section: Introductionmentioning

confidence: 99%

Guidance and Self‐Sorting of Active Swimmers: 3D Periodic Arrays Increase Persistence Length of Human Sperm Selecting for the Fittest

et al. 2017

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Male infertility is a reproductive disease, and existing clinical solutions for this condition often involve long and cumbersome sperm sorting methods, including preprocessing and centrifugation‐based steps. These methods also fall short when sorting for sperm free of reactive oxygen species, DNA damage, and epigenetic aberrations. Although several microfluidic platforms exist, they suffer from structural complexities, i.e., pumps or chemoattractants, setting insurmountable barriers to clinical adoption. Inspired by the natural filter‐like capabilities of the female reproductive tract for sperm selection, a model‐driven design, featuring pillar arrays that efficiently and noninvasively isolate highly motile and morphologically normal sperm, with lower epigenetic global methylation, from raw semen, is presented. The Simple Periodic ARray for Trapping And isolatioN (SPARTAN) created here modulates the directional persistence of sperm, increasing the spatial separation between progressive and nonprogressive motile sperm populations within an unprecedentedly short 10 min assay time. With over 99% motility of sorted sperm, a 5‐fold improvement in morphology, 3‐fold increase in nuclear maturity, and 2–4‐fold enhancement in DNA integrity, SPARTAN offers to standardize sperm selection while eliminating operator‐to‐operator variations, centrifugation, and flow. SPARTAN can also be applied in other areas, including conservation ecology, breeding of farm animals, and design of flagellar microrobots for diagnostics.

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“…Another recent meta‐analysis (Santi, Vincentis, Magnani, & Spaggiari, ) including 24 studies also showed that male infertility is associated with abnormal sperm DNA methylation of H19, MEST and SNRPN genes. Other studies reported that DNA methylation levels of imprinted genes IGF2, PEG3, ZAC, LIT1, SNRPN and non‐imprinted repetitive elements, such as LINEs and ALU , were altered in abnormal spermatozoa (Boissonnas et al, ; El Hajj et al, ; Kobayashi et al, ; Urdinguio et al, ; Xu et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Specific epigenetic alterations of the IGF2‐H19 locus were detected in patients with teratozoospermia and oligo‐astheno‐teratozoospermia (Boissonnas et al, ). Xu et al () reported abnormal methylation levels of P16, MEST, GNAS, FAM50B and LINE‐1 DMRs in patients with asthenozoospermia. For idiopathic non‐obstructive azoospermia (NOA) patients, the evaluation of epigenetic alteration relied on testicular tissue because they have no spermatozoa in their semen (Wu, Ding, Tan, Li, & Xiong, ).…”

Section: Discussionmentioning

confidence: 99%

“…Epigenetics has been implicated in the aetiology of male idiopathic infertility (Carrell, ). Recent studies showed that aberrant DNA methylation, particularly at imprinted loci, has been related to poor semen quality (Boissonnas et al, ; Klaver et al, ; Marques et al, ; Xu et al, ). In addition, aberrant sperm DNA methylation is linked to reduced fertilisation rates and impaired embryonic developmental potential (Laurentino, Borgmann, & Gromoll, ).…”

Section: Introductionmentioning

confidence: 99%

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Methylation levels ofIGF2andKCNQ1in spermatozoa from infertile men are associated with sperm DNA damage

Pan

et al. 2019

Andrologia

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Abnormal imprinted genes methylation in spermatozoa has been shown to be associated with subfertility. However, the relationship between sperm DNA damage and specific imprinted genes methylation remains unclear. In this study, DNA methylation levels were determined at seven imprinted genes loci (H19, INS‐IGF2, KCNQ1, MEG3, MEST, PEG3 and SNRPN) in 66 semen samples using the MSRE‐qPCR method. The semen samples were divided into two groups according to the threshold value (25%) of DNA fragmentation index (DFI). We found that the mean methylation level at IGF2 (cg17037101) in the group with DFI ≥ 25% was lower than that in the group with DFI < 25% (13.7 ± 3% vs. 31.5 ± 5.3%, p = 0.0053). However, the methylation levels of other CpGs did not differ from the imprinted genes. Correlation analysis of DFI with the methylation levels of imprinted genes demonstrated that the IGF2 (cg17037101) methylation level was negatively correlated with sperm DFI (r = −0.448, p = 0.0038), and the KCNQ1 (cg24932449) methylation level was positively correlated with sperm DFI (r = 0.354, p = 0.0273). Our results suggest that the aberrant methylation of IGF2 and KCNQ1 genes may be associated with sperm DNA damage.

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DNA methylation levels of imprinted and nonimprinted genes DMRs associated with defective human spermatozoa

Cited by 41 publications

References 31 publications

DNA methylation in spermatogenesis and male infertility

DNA methylation in spermatogenesis and male infertility

Guidance and Self‐Sorting of Active Swimmers: 3D Periodic Arrays Increase Persistence Length of Human Sperm Selecting for the Fittest

Methylation levels ofIGF2andKCNQ1in spermatozoa from infertile men are associated with sperm DNA damage

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