Fig. 1
Epigenetic regulation throughout the S. mansoni cycle: The figure shows some epigenetic marks enriched in the different stages of S. mansoni and some miRNAs involved in parasite-host interaction. Larval stage mucins (SmPoMuc) interact with snail immunity proteins. The intermediate host has downregulation of several miRNA and piRNA biogenesis pathway proteins during miracidium penetration and also during the subsequent stages of development. The most enriched epigenetic marks in cercariae are characteristics of gene silencing. In schistosomes, miRNAs 277 and 4989 may be related to adult worm development. In adults there is an enrichment of epigenetic marks associated with eucromatization. There are miRNAs from the parasite that have already been found in human serum and have been proposed as possible diagnostic biomarkers.
Table 1
Main enzymes and reactions involved in epigenetic processes in S. mansoni.
| Enzyme type | Reaction catalyzed | Reaction example | Access code or reference |
|---|---|---|---|
| DNMT2 | DNA methylation | Cytosine + S-Adenosyl-L-methionine DNA- methyltransferase Cytosine-CH3 | (Geyer et al., 2011) Smp_198180 |
| HDACs | Histone deacetylation | HO + N6-acetyl-L-lysyl-[histone] = 2acetate + L-lysyl-[histone] | SmHDAC1 Smp_005210; SmHDAC3 Smp_093280; SmHDAC8 Smp_091990; (Oger et al., 2008) |
| HAT | Catalyzes acetylation in lysines of histones and other proteins | Zinc ion binding Bromodomain Acetyltransferase activity | AY337317 Smp_105910 (Bertin et al., 2006; Maciel et al., 2004) |
| HMT PRMT | Protein arginine N-methyltransferase 1 S-adenosyl-L-methionine Methyltransferase . Peptidyl-arginine N-methylation | Catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA). | Smp_070340 Smp_029240.2 Smp_025550 Smp_171150 Cabezas-Cruz et al., 2014 |
| PTKs | Phosphorylation of tyrosine protein diversity | ATP + a protein-L-tyrosine ADP + a protein-L-tyrosine phosphate | (Avelar et al., 2011) |
| Ubiquitin- conjugating enzymes (Ub-E2) | Catalyzes the intermediate step of protein ubiquitination | S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [E2 ubiquitin-conjugating enzyme]-L-cysteine = [E1 ubiquitin-activating enzyme]-L-cysteine + S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine. | (Costa et al., 2015) |
| UCHs, USPs, OTUs, MJDs | Involved in ubiquitin processing, in the recovery of modified ubiquitin trapped in inactive forms, and in the recycling of ubiquitin monomers from polyubiquitinated chains DNA repair, cell-cycle control, endocytosis, transcription and protein degradation by the proteasome | Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Glycine of ubiquitin | (Pereira et al., 2015) |
| HMT PKMT | Protein lysine methyltransferase (PKMT) | L-lysyl-[protein] + S-adenosyl-L- methionine = H+ + N6-methyl-L-lysyl- [protein] + S-adenosyl-L-homocysteine | (Smp _000700) (Whatley et al., 2019) |
| KDM | Lysine specific demethylase | Demethylation of 'Lys-27' of H3 and appendant methylation of 'Lys-4' of histone H3, in agreement with recruitment of the PRC1 complex and monoubiquitination of histone H2A | (Smp_034000) (Lobo-Silva et al., 2020) |
[i] DNMTs = DNA-methyl-transferase, Ub-E2 = ubiquitin-protein conjugation, HAT = Histone acetyltransferase, HDAC = Histone deacetylase MJDs = Machado-Joseph disease proteases, OTUs = ovarian tumor proteases, PTKs = Protein tyrosine kinases, UCHs = Ubiquitin C-terminal hydrolases, USPs = ubiquitin-specific proteases
Table 2
The epigenetic influence in different stages of the S. mansoni life cycle and its involvement in several mechanisms.
| Life cycle stage | Developmental stage | Epigenetic Findings | Gene | Mechanisms | Reference |
|---|---|---|---|---|---|
| Mammal host | Mature egg | Epigenetic readers characterization | SmMBD2/3 and SmCBX | Neoblasts proliferation and normal eggs production | (Geyer et al., 2018) |
| Schistosomula | miRNA enriched in RNA-seq analysis: oesophagus and tegumental cells derived. | sma-miR-277/4989 | Downregulation in paired worms and upregulation in virgin worms – schistosomula to adult transition | Protasio et al., 2017 | |
| Adult worm | miRNAs parasite-derived in definitive host serum | miR-277, miR-3479-3p and bantam | Macrophage proliferation, TNFα increase and ovary development | Hoy et al., 2014, Zhu et al., 2016 Liu et al., 2019 | |
| Free life | Miracidium | Mucin epigenetic polymorphisms | SmPomucs | Neutralizing snail immune system | (Fneich et al., 2016; Perrin et al., 2013) |
| Cercaria | miRNA presenting high rates in a specific stage | miR-71 | Stage specific functions | Mu et al., 2019 | |
| Snail Host | Sporocyst | lncRNAs RNA-seq | Unique sets in sporocysts e.g SmLINC181757 SmLINC180219 SmLINC180220 SmLINC180221 SmLINC180222 | Asexual reproduction, Kinome, Stage specific function | Kim et al., 2020 |
Fig. 2
Important advances in DNA methylation, histone modifications, and Non-coding RNAs related to Schistosoma in the last 20 years.