Developmental Biology & Stem CellsDNA Methylation and HydroxymethylationHistone ModificationsRegulatory RNA

Don’t forget all that dad has done for you.. and your epigenome.. this father’s day!

Sperm epigeneticsIn mammals, the recognition and fusion between the sperm from the father and the oocyte from the mother gives rise to offspring. Therefore, the production of functional, flagella-containing motile sperm is the prerequisite for successful fertilization in nature. In human females, there is typically only one oocyte ovulated during each menstrual cycle. Rodents on the other hand tend to ovulate a dozen at a time. In contrast to this limited number of oocytes, males can continuously produce millions of sperm in the testis, which actively transit to the epididymis and are transiently stored in the cauda part of the epididymis prior to ejaculation. When considering sheer numbers, it would seem that men are less likely to encounter a fertility problem compared with their female partners, as women have a limited number of oocytes ovulated in their lifetime. However, it is commonly observed in the clinic that both men and women equally experience infertility.

Sperm production consists of three consecutive developmental stages: mitosis of spermatogonia, meiosis of spermatocytes and post-meiotic spermatid maturation. Following meiosis, one spermatogonial cell gives rise to four round haploid spermatids, which further elongate and shed the majority of the cytoplasm to develop into mature sperm, a process known as spermiogenesis. This process is unique in that haploid spermatid undergoes a dramatic morphological change (formation of acrosome and flagella tail), as well as repackaging of the chromatin architecture (transition from nucleo-chromatin to protamine-chromatin structure). Therefore, through spermiogenesis, sperm acquire two capabilities: “swimming” ability in order to transit into the female reproductive tract to fertilize the eggs and, more importantly, chromatin condensation and “epigenetic decoration” to protect the genome stability and to prepare for early pre-implantation embryonic development. In a recent publication, Bao et al. summarized the epigenetic players, such as histone variants and post-translational modifications (PTMs), that synergistically cooperate to facilitate histone replacement by basic proteins-protamines.

With the exception of histone H4, all other canonical histones (H1, H2A, H2B and H3) have a diversity of variants, which are abundantly expressed in testis, especially during haploid spermatid maturation. Genetic evidence using gene knockout (KO) mouse models unveiled that perturbation of histone variants often led to defective histone-to-protamine transition and, consequently, male sterility. In addition to histone variants, recent large-scale LC/MS studies discovered a wide range of novel PTMs on basic proteins (histone, transition proteins and protamines) present throughout different stages of haploid spermatid development. Interestingly, a few PTMs appear to be exclusively detected right before the histone-to-protamine transition process, such as H3K79me31. PTMs are usually “read” by the effector proteins (readers) and confer the signal downstream. Thus, it is highly likely that those newly synthesized PTMs, at least in part, take part in the histone substitution by protamines.

Naturally, sperm with defective “epigenomes” not only cause male infertility, but also have a profound impact on the health of offspring. Traditionally, it has been recognized that sperm simply serve as a “vehicle” to provide paternal “genetic DNA materials” to the oocytes upon fertilization, because the majority of cytoplasm were removed in the mature sperm. However, in recent years, scientists have found that sperm also carry important epigenetic information that can be transmitted to the next generation and influence health outcomes.2,3 In a pioneer study by Kimmins et al.,2 scientists treated male mice with folate-sufficient and folate-deficient diets, and found that paternal folate deficiency correlated with increased birth defects in the offspring. Genome-wide DNA methylation analysis identified a set of differentially methylated genes related to cancer, diabetes, autism and schizophrenia in the folate-deficient sperm. Since dietary folate can modulate levels of S-adenosyl methionine, the principal methyl donor for methylation, this study suggests that adequate folate supplementation is equally important to men and women, before pregnancy.4

Non-coding RNAs may also be another layer of epigenetic regulation transmitted to the offspring through paternal inheritance. Two recent studies published in Science discovered that offspring health outcomes can be affected by the father’s diet through sperm-derived tRNA fragments (tsRNAs), which represent 80% of total small RNA in the sperm head.5,6 Mechanisms underlying how paternal tRNA fragments interfere with gene expression remain enigmatic. However, paternal mouse models with high-fat diets (HFD) have a much higher risk of transmitting diet-induced metabolic disorders to the next generation through modulating paternal tsRNAs levels and associated RNA modifications in the sperm. This evidence unequivocally demonstrates that sperm carry crucial epigenetic information that is as equally important as that in maternal oocytes.5,6

Defective epigenetic organization of sperm chromatin, and the infertility resulting from genetic and environmental risk factors may function as a natural selection mechanism to prevent developmental disorders and negative health outcomes in offspring. Furthermore, the studies discussed above suggest that men must adapt to a balanced, healthy lifestyle prior to impregnation in order to produce a healthy baby. This is an important consideration that must be addressed in the use of assisted reproductive technologies (ART), such as intracytoplasmic sperm injection “ICSI” or round spermatid injection “ROSI”,7 that have been widely adopted in fertility clinics worldwide. We must be cautious of the potential risks that come with making infertile sperm fertile. Because infertility may be due to a dysfunctional epigenome, making these sperm fertile again may allow the inheritance of defective epigenomes and may negatively impact offspring conceived via ART. From an epigenetic point of view, rather than simply making all infertile sperm fertile, it might be better to pick up more morphologically “normal” sperm cells for ART purposes. Remember – healthy sperm, healthy baby!

Jianqiang Bao
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, United States of America

Original Article:

Bao J, Bedford MT. Epigenetic regulation of the histone-to-protamine transition during Spermiogenesis. Reproduction 2016.


1. Dottermusch-Heidel, C., Klaus, E., Gonzalez, N., Bhushan, S., Meinhardt, A., Bergmann, M., Renkawitz-Pohl, R., Rathke, C., & Steger, K. (2014). H3K79 methylation directly precedes the histone-to-protamine transition in mammalian spermatids and is sensitive to bacterial infections Andrology, 2 (5), 655-665 DOI: 10.1111/j.2047-2927.2014.00248.x

2. Donkin, I., Versteyhe, S., Ingerslev, L., Qian, K., Mechta, M., Nordkap, L., Mortensen, B., Appel, E., Jørgensen, N., Kristiansen, V., Hansen, T., Workman, C., Zierath, J., & Barrès, R. (2016). Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans Cell Metabolism, 23 (2), 369-378 DOI: 10.1016/j.cmet.2015.11.004

3. Rodgers, A., Morgan, C., Leu, N., & Bale, T. (2015). Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress Proceedings of the National Academy of Sciences, 112 (44), 13699-13704 DOI: 10.1073/pnas.1508347112

4. Lambrot, R., Xu, C., Saint-Phar, S., Chountalos, G., Cohen, T., Paquet, M., Suderman, M., Hallett, M., & Kimmins, S. (2013). Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes Nature Communications, 4 DOI: 10.1038/ncomms3889

5. Chen, Q., Yan, M., Cao, Z., Li, X., Zhang, Y., Shi, J., Feng, G., Peng, H., Zhang, X., Zhang, Y., Qian, J., Duan, E., Zhai, Q., & Zhou, Q. (2015). Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder Science, 351 (6271), 397-400 DOI: 10.1126/science.aad7977

6. Sharma, U., Conine, C., Shea, J., Boskovic, A., Derr, A., Bing, X., Belleannee, C., Kucukural, A., Serra, R., Sun, F., Song, L., Carone, B., Ricci, E., Li, X., Fauquier, L., Moore, M., Sullivan, R., Mello, C., Garber, M., & Rando, O. (2015). Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals Science, 351 (6271), 391-396 DOI: 10.1126/science.aad6780

7. Tanaka A, Nagayoshi M, Takemoto Y, Tanaka I, Kusunoki H, Watanabe S, Kuroda K, Takeda S, Ito M, & Yanagimachi R (2015). Fourteen babies born after round spermatid injection into human oocytes. Proceedings of the National Academy of Sciences of the United States of America, 112 (47), 14629-34 PMID: 26575628


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Jianqiang Bao

Jianqiang Bao