Sperm epigenome and its potential role in transgenerational inheritance

Abstract

Epigenetics regulation is generally referred to DNA methylation, histone modification and non-coding RNA, which play important roles in chromatin management and gene expression. Recent studies have found that sperm genome is dynamically regulated by a variety of epigenetics mechanisms. More importantly, emerging evidences suggest that certain epigenetics information could be transmitted from sperm to offspring for limited generations. Here, we have overviewed the epigenetics mechanisms involved in spermatogenesis and after fertilization, and the potential underlining mechanisms of epigenetic inheritance. In the first part, we summarized the current understanding of the regulation of DNA methylation, histone modification and small non-coding RNA in spermatogenesis and early embryonic development. This part started from the establishment of sperm DNA methylome and the reprogramming of paternal DNA methylome after fertilization. We briefly described how DNA methylation is regulated by DNMT and TET proteins, and its role in silencing repetitive elements and imprinting genes. We also summarized the two rounds of reprogramming of DNA methylation after fertilization. During the first round of reprogramming, most DNA methylation signature from germ cells is erased, and somatic DNA methylome is then re-established. The second round occurring from primordial germ cells to germ cells, during which DNA methylation at imprinted genes is erased, and germ cell specific DNA methylome is then re-established. It is generally believed that the two rounds of reprogramming establish the proper DNA methylome for germ cell formation. We then reviewed the specific pattern and functional involvement of sperm histone modifications and histone variants. During sperm maturation, most histones undergo acetylation-mediated degradation and replaced by protamine, resulting in only ~10% genome with retained nucleosomes. The remaining nucleosomes contain canonic histones and various histone variants, including TH2A, TH2B, H3t, H3.3, etc. Importantly, sperm histones are also modified, such as H3K4me3, H3K27me3, H3K27ac and H4S1ph. Some modifications are deposited to developmental genes and imprinting loci, while others are thought to control sperm genome accessibility and compaction. Exemplified by transgenerational developmental defects caused by sperm H3K4me2 disruption, proper histone modification patterning in sperm is thought to be critical for early development. We also summarized the recent discoveries in the regulation of H3K4me3 and H3K27me3 from fertilized mouse oocytes to ICM, revealing a highly dynamic and regulated nature of histone modification during early development. The recent progresses of small non-coding RNA regulation in sperm are also included in this review. For instance, piRNAs are required for heterochromatin formation and gene silencing, especially retrotransposon silencing during spermatogenesis; certain miRNAs, like miR-290-miR295 and miRNA-34b-5p , are required for proper meiosis and cell cycle regulation during spermatogenesis; importantly, tRNA-derived small RNAs (tsRNAs) in sperm were found responsive to paternal diet and able to influence the offspring’s metabolism. In the second part, we focused on the environmental impacts on sperm epigenome and potential mechanisms of transgenerational inheritance. To date, several studies have implied that diet, pressure and chemical exposure can alter sperm epigenome, which could potentially be inherited through generations. For example, paternal diet is demonstrated to affect offspring’s metabolism. Paternal physiological stress, such as restraint stress or early trauma, could influence offspring’s metabolism or behavior through altered paternal sperm DNA methylation and miRNAs. Additionally, altered sperm DNA methylation has been observed in male rats suffered from utero undernourishment, which could contribute to the high risk of type II diabetes in the offspring. Taken together, we just started to understand the potential role of epigenetics involving in the transgenerational response to environmental changes. Future epigenomic investigations of sperm, as well as oocyte and zygote, should provide more mechanistic insights in how environment could influence the genome and how the effect might be inherited.