Sperm epigenetics and male infertility: unraveling the molecular puzzle

Abstract

Background: The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors.

Main body: The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility.

Conclusion: In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues.

Keywords: DNA methylation; Epigenetics; Histone modifications; Infertility; Non-coding RNAs; Sperm.

Fig. 1

Epigenetic events during spermatogenesis. The genetic material of primordial germ cells undergoes demethylation as they migrate to the genital ridge. Global DNA methylation is established in prospermatogonia and completed before birth. Specialized histone variants are active during sperm development until the elongated spermatid stage, when they are gradually replaced by transitional proteins, preparing for transition to protamine and chromatin compaction. PGC: Primordial germ cells

Fig. 2

ncRNAs, histone-to-protamine transition, DNA methylation, and histone modifications are the primary epigenetic mechanisms controlling a variety of sperm activities. A complex pool of ncRNAs contain sperm-related epigenetic information. Both spermatogenesis and post-testicular maturation processes result in the acquisition of this RNA-mediated epigenetic data (A). Throughout spermatogenesis, the majority of histones undergo substitution with PRMs; however, a small fraction remains in the sperm DNA (B). Within sperm chromatin, a wide range of post-translational modifications take place in the remaining histones (C). DNA methylation is another epigenetic marker that refers to the presence of 5mC in the DNA, which can influence the expression of genes (D). ncRNAs: non-coding RNAs, PRM: Protamine, 5mC: 5-methylcytosine, Ac: Acetylation, Me: Methylation, P: Phosphorylation, Ub: Ubiquitination

Fig. 3

miRNAs biogenesis. Pri-miRNAs are transcribed by RNA polymerase II/III. Following transcription, a microprocessor complex comprising an RNA-binding protein, DGCR8, and a ribonuclease III enzyme called Drosha cleaves the base of the pri-miRNA hairpin, generating pre-miRNA. These are then exported to the cytoplasm by XPO5/RanGTP complex, where an RNase III endonuclease, Dicer, removes their terminal loop. Subsequently, miRNAs are integrated into the RISC complex, which includes proteins like Ago2. Ago2 plays a crucial role in either retaining or discarding one strand of the miRNA duplex. The retained guide strand is employed by the RISC for ongoing functionalities, whereas the discarded passenger strand undergoes degradation. miRNA: microRNA, Pri-miRNAs: Primary miRNAs, DGCR8: DiGeorge syndrome critical region 8, Pre-miRNA: Precursor miRNA, XPO5: exportin 5, RISC: RNA-induced silencing complex, Ago2: Argonaute RISC catalytic component 2

Fig. 4

Mechanism of action of lncRNAs Decoy lncRNAs attach to miRNAs or TFs to stop them from engaging with their targets. (A). Guide lncRNAs bind to their target proteins to form an RNP complex that is directed to a certain genomic locus to control gene transcription (B). Scaffold lncRNAs construct scaffolding complexes in collaboration with other molecules like chromatin remodeling proteins, to regulate gene expression via epigenetic processes such as histone modification (C). Signal lncRNAs regulate gene expression in response to a range of stimuli by directly binding to DNA or by forming complexes with other molecules (D). SINEUP lncRNAs form translational initiation complexes that promote translation of their target mRNAs (E). lncRNAs: Long non-coding RNAs, miRNAs: microRNAs, TF: Transcription factor, RNP: Ribonucleoprotein

Fig. 5

Biogenesis and main functions of piRNAs. Several factors, such as Moon, TRF2, TREX, and UAP56, participate in the generation of piRNA precursors from piRNA clusters. Subsequently, the RNA helicase Armi resolves the secondary structures present in these precursors, and then Zucchini adds a 5’ monophosphate to their structure. The maturation process of piRNAs occurs when they undergo cleavage using the 3’ to 5’ exonuclease Nibbler after being loaded onto the PIWI protein. piRNAs: Piwi-interacting RNAs, Moon: Moonshiner, TRF2: TATA-box binding protein (TBP)-related factor 2, TREX: Three prime repair exonuclease, UAP56: 56-kDa U2AF-associated protein, Armi: Armitage, Zuc: Zucchini, Nbr: Nibbler, Aub: Aubergine

Fig. 6

Biogenesis and main functions of tsRNAs. Depending on their length and the specific region in which endonucleases cleave tRNAs or pre-tRNAs, two primary forms of tsRNAs can be generated: (i) Cleavage of tRNA by ANG and Rny1 ribonucleases near or within the anticodon loop results in the production of 5’- or 3’- tiRNA halves with a length of 30–40 nucleotides. (ii) tRFs are sequences of 18–22 nucleotides generated when nucleases like Dicer or ANG, cleave tRNA at any location. tsRNAs: tRNA-derived small RNAs, ANG: Angiopoietin, tiRNAs: tRNA-derived stress-induced RNAs, tRFs: tRNA-derived fragments,