Epigenetic studies in insects and the valproic acid perspective

Estudos epigenéticos em insetos e a perspectiva do ácido valpróico

Abstract

Valproic acid in association with sodium valproate (VPA) is an important anticonvulsant drug used for decades to treat neurological disorders. VPA also acts as an epigenetic modulator by inhibiting histone deacetylases, permitting histone acetylation, affecting the DNA and histone methylation status and gene expression, and inducing chromatin remodeling. Insects represent an important animal model for studies in several areas of science. Their high phenotypic plasticity makes them alternative models for epigenetic studies. This brief review emphasizes recent reports on insect epigenetics and the contribution of studies on the VPA action in insects, including effects on epigenetic markers, extending the pharmacological understanding of the potential of this drug, and demonstrating the usefulness of insects as an alternative animal model to drug studies.

Keywords:
sodium valproate; DNA methylation; histone modification; non-coding RNAs; chromatin

Resumo

O ácido valproico associado ao valproato de sódio (VPA) é um importante agente anticonvulsivo usado há décadas no tratamento de distúrbios neurológicos. Também atua como um modulador epigenético ao inibir as desacetilases de histonas, permitindo a acetilaçao de histonas, afetando o estado de metilação do DNA e das histonas e a expressão gênica, e induzindo a remodelação da cromatina. Os insetos representam um importante modelo animal para estudos em diversas áreas da ciência e dada a sua alta plasticidade fenotípica os torna modelos alternativos para estudos epigenéticos e de resposta a agentes moduladores epigenéticos. Esta breve revisão enfatiza relatos recentes sobre epigenética em insetos e a contribuição de estudos sobre a ação do VPA nesse grupo animal, incluindo efeitos sobre marcadores epigenéticos, estendendo a compreensão farmacológica do potencial desta droga e demonstrando a utilidade dos insetos como um modelo animal alternativo para estudos de drogas.

Palavras-chave:
valproato de sódio; metilação do DNA; modificação de histonas; RNAs não-codificantes; cromatina

1. Epigenetics: General Concepts

Epigenetics is specifically concerned with reversible changes in gene expression or silencing that do not involve changes in DNA base sequences and that furnish a cell memory that goes beyond the potential of the DNA genetic code and that can be heritable through mitosis or meiosis, passing to the next generation (Wu and Morris, 2001). Gene expression can thus be altered without modification of the genetic code.

The mechanisms of epigenetic changes include 1) DNA methylation, which results from the incorporation of a methyl group to the cytosine carbon 5, mostly in cytosine followed by guanine (CpG) and leading to the formation of 5-methylcytosine (5mC), 2) histone post-translational modifications, including acetylation and methylation, and histone variants, and 3) mechanisms mediated by non-coding RNAs. All these epigenetic mechanisms with respective effects on cells and organisms have been widely described and the subject of several reviews, with predominant application to vertebrate models. In insects, epigenetic studies have been restricted to a few model groups and species and even in these cases, a few reports have been addressed to disease vectors (Sharakhov and Sharakhova, 2015), possibly because non-efficient functional validation tools are sufficiently available for these non-model organisms (Richard et al., 2021). It is always worth mentioning that the pioneering studies and concepts of Waddington, who coined the term Epigenetics in 1942 (Waddington, 2012), refer to the environmental influences on the development of phenotype in Drosophila melanogaster (Tronick and Hunter, 2016).

Epigenetic mechanisms regulate the development of extreme phenotypic divergences and environmental adaptations, permitting dynamic changes of insect phenotype, conservation of insect forms and functions, and interconnections with other forms of biological regulation (Villagra and Frías-Lasserre, 2020). Regarding social insects, including ants, bees, wasps, and termites, epigenetics has revealed an important role in eusocial societies, participating in caste determination and phenotypic plasticity, and leading to the evolutionary success of these groups (Bonasio, 2014; Yan et al., 2015; Sieber et al., 2021).

In this brief review, we summarize some relevant aspects of the epigenetic mechanisms reported for insects and the emerging role of drugs like valproic acid, that while perturbing the epigenome in human and animal cells, may contribute to a better understanding of the diversity of the epigenetic metabolic pathways followed by these drugs when using insects as complimentary research models.

2. Epigenetic Markers in Insects

2.1. DNA methylation

DNA methylation is generally associated with the repression of gene activity and depends on the action of enzymes of the DNA methyltransferase (DNMT) family. Although it does not cause changes in the DNA sequence, it significantly affects the interaction of DNA with proteins (Kozeretska et al., 2017). The analysis of the DNA methylation and demethylation processes in insects indicates that these epigenetic events not only allow them to control and tolerate stress insults but also furnish the ability to change their structures and behavior, and affecting their offspring (Villagra and Frias-Lasserre, 2020).

Even though DNA methylation is a widely heritable form of epigenetic information especially residing in the CpG context in several organisms, it is absent or reduced from the genomes of many insect species (Suzuki and Bird, 2008; Bewick et al., 2017; Provataris et al., 2018; Glastad et al., 2019). In dipterans, including Drosophila melanogaster, there is little presence of DNA methylation (Lyko et al., 2000; Provataris et al., 2018). In the beetle Tribolium castaneum, the levels of DNA methylation are also close to zero (Schulz et al., 2018). In the hemipteran species Aphis nerii and Triatoma infestans, although cytosine methylation is revealed in euchromatin, it is not identified in heterochromatin (Alvarenga et al., 2011; Mandrioli et al., 2011).

In highly eusocial bees, the bumblebee Bombus terrestris, ants, and non-social wasps, where DNA methylation was confirmed, shared methylation sites associated with key biological processes (development, caste differentiation, lifespan, sex determination, cognition and memory, among others) have been suggested by several authors (Villagra and Frias-Lasserre, 2020 – review, Araujo and Arias, 2021), although DNA methylation as a causal role in the divergent development of queen and worker castes has been questioned for honeybees (Oldroyd and Yagound, 2021). In the larval genome of Apis mellifera around 49 million cytosines are present, of which only 90,000 cytosines are methylated; genomic analysis showed 38 differentially methylated genes between queen larvae and worker larvae associated with differentiation of specific organs, including those involved in reproduction, morphology, and vision differentiation (Wang et al., 2020). In addition, involvement of non-CG methylation in bee eusociality has recently been proposed (Araujo and Arias, 2021).

Planococcus citri, a citrus mealybug that exhibits a sex-specific genomic imprinting with the elimination of the entire paternal genome during spermatogenesis, has been analyzed with reference to its DNA methylation profile (Bain et al., 2021). Genome-wide-analysis of sex-specific gene expression and DNA methylome performed in adult specimens revealed that while males exhibit overall higher levels of DNA methylation manifested at more uniform low sites across the genome, females display more targeted higher levels of DNA methylation (Bain et al., 2021). These findings were suggested to be associated with chromosomal differences caused by the paternal genome elimination and possibly related to ploidy compensation.

In contrast to vertebrates in which most DNA methylation occurs in both intragenic and intergenic regions, in insects DNA methylation occurs within gene bodies affecting exon sequences in holometabolous species, or occurs largely in the genome in hemimetabolous species (Glastad et al., 2019). The functional significance of this event is yet not clear, especially considering that the DNA methylation events have a general effect on transcription factor binding and recruitment which in turn requires patterns of transcript splicing (Glastad et al., 2019).

2.2. Histone modifications

Histones are basic proteins that make complexes with the DNA forming chromatin in eukaryotes; they not only play a structural role by packaging the DNA but also represent regulators of the DNA function. Post-translational modifications of histones, which include acetylation, methylation, phosphorylation, and ubiquitination, among others, of several of their different amino acid residues, and that are mainly focused on histones H3 and H4, are involved in the regulation of cell differentiation and disease (Lennartsson and Ekwall, 2009). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes responsible for inserting and removing the acetyl groups, in and from, respectively, the amino acids of histones. Histone acetylation mostly affecting lysine (K) residues reduces the electrostatic binding of histones to DNA, facilitating the accessibility of binding factors to DNA and permitting its transcription. Histone methylation, on the other hand, may be associated with actively expressed or repressed genes depending on the metabolized residues, the number of inserted -CH₃ groups to these residues, and wherein the genome such inserted groups are associated. For example, H3K27me is correlated with active genes whereas H3K27me3 is associated with silent genes; H3K9me3 correlates with repressed genes when present at the gene promoter but correlates with gene expression when enriched within the body of a gene (Black and Whetstine, 2011). Non-histone proteins, for instance, the heterochromatin protein HP1, may associate with histone modifications, participating in chromatin structure and remodeling (Felisbino et al., 2014).

It appears that histone modifications or an alternative sequence variant of a histone may be more involved in the mediation of phenotypic plasticity in insects than DNA methylation (Glastad et al., 2019). However, except for flies of the genera Drosophila and Anopheles, a few studies are still devoted to exploring post-translational histone modifications in association with transcription control and the regulation of chromatin structure and function (Swaminathan et al., 2012; Neafsey et al., 2015; Sharakhov and Sharakhova, 2015). In Drosophila, different members of HDACs are related to specific functions and processes such as aging, segmentation, suppression of apoptosis, and circadian rhythms, and the histone demethylase KDM5 is responsible for regulating social behavior through immunological maintenance of the intestinal microbiota, and development control (Chen et al., 2019; Drelon et al., 2019).

Epigenetic research to evaluate interferences of pathogenic bacteria on the regulation of HDACs and HATs in insects demonstrated that histone acetylation/deacetylation intervenes in transcriptional reprogramming during metamorphosis and in response to injuries and infections, which can modulate directly responses on immunity and development (Mukherjee et al., 2015, 2017). Histone acetylation can also play an important role in chromosomal imprinting in the germline of sciarid flies; in male meiosis, the maternal chromosomes are highly acetylated for histones H3 and H4, whereas the entire set of the paternal chromosomes that will undergo elimination appears under-acetylated (Goday and Ruiz, 2002; Matsuura, 2020). Locusta migratoria represents one of the richest species in histone-modifying enzymes, that are highly expressed in male eggs and testes, and that can play important roles in embryogenesis and spermatogenesis (Guo et al., 2016; Lo et al., 2018).

Twelve HDACs have been identified in the coleopteran Tribolium castaneum. HDAC1, particularly, plays a role in the regulation of cellular processes necessary for the postembryonic development of this insect, affecting the acetylation status of histones and suppressing the expression of genes involved in the action of the juvenile hormone (George et al., 2019). In the absence of juvenile hormone, multiprotein complexes suppress the expression of juvenile hormone response genes. On the other hand, suppression of the expression of the HDAC1 gene by juvenile hormone induces increase in the acetylation levels of core histones regulating the expression of juvenile hormone response genes such as Kr-h1 (George et al., 2019). These findings demonstrate that the juvenile hormone action is affected by epigenetic modifications (George et al., 2019).

Differential identification of acetylated H3K9, H4K8 and H4K16 and mono-, di-and trimethylated H3K9 (H3K9me/me2/me3) between euchromatin and heterochromatin has been reported in the hemipteran species Triatoma infestans and Panstrongylus megistus, vectors of Chagas disease, and are consistent with the transcriptionally active and relatively inert status, respectively, of these chromatin compartments (Alvarenga et al., 2016, 2018). More details on histone acetylation, histone methylation, and histone phosphorylation in insects have been recently revised by Villagra and Frías-Lasserre (2020).

Histone variants also alter gene expression. Variants of the canonic histone H2A, for instance, affect the chromatin repeating elements, the nucleosomes, resulting in increased accessibility of the DNA. Histone variants have been detected in Drosophila and are considered promising candidates for investigation in other insect species (Glastad et al., 2019).

2.3. Non-coding RNAs

Regarding the epigenetic effects carried out by non-coding RNAs, small RNAs like microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), with 20-40 nucleotides, and long non-coding RNAs (lncRNAs), with more than 200 nucleotides, have particularly been identified in the regulation of gene expression of insects, especially in Drosophila (Chambeyron and Seitz, 2014; Kelleher, 2016; Glastad et al., 2019; Villagra and Frías-Lasserre, 2020). miRNAs are post-transcriptional regulators of gene expression by interacting with mRNAs and affecting protein levels (Bartel, 2009; Asgari, 2018; Richard et al., 2021). A review by Asgari (2018) has emphasized that although studies of insect miRNAs are recent, they are already revealing involvement of these molecules in development, reproduction, caste determination, lifespan, insecticide resistance and immune responses to infection, among other physiological events. Caste-specific expression of miRNAs has been reported in ants, honeybees, and bumblebees (Guo et al., 2013), ranging from 257 in the silkworm Bombyx mori, to 883 in Locusta migratoria (Wang et al., 2015; Wang et al., 2019).

Recent studies have shown the use of an artificial miRNA (amiRNA) approach for gene silencing to generate insect pest-resistant tomato plants. Plant amiRNAs are produced by expression of a miRNA gene genetically modified to silence a desired target gene. amiRNAs manipulate gene functions because of their efficiency and specificity to decrease target gene expression. Plant amiRNAs are thus a potential strategy for engineering plant resistance to virus and insects (Agrawal et al., 2015; Yogindran and Rajam, 2021). Helicoverpa armigera specimens that were continuously fed with tomato leaves expressing amiRNA-319a-HaEcR, showed a reduction in the target gene (ecdysone receptor EcR) transcripts, affecting the general growth and survival of this lepidopteran pest. Furthermore, the expression of downstream genes involved in the ecdysone signaling pathway (E74A, Et4B, BR-C7 and HR3) was affected. Interference in the ecdysone signaling results in impaired embryogenesis and disrupted metamorphosis. These results helped to understand the role played by ecdysone receptors as well as the effectiveness of amiRNA technology in the control of H. armigera (Agrawal et al., 2015; Yogindran and Rajam, 2021).

Following the same line of reasoning on pest control, a methodology based on pre-microRNA proved to be efficient in controlling herbivorous insect pests. The study was conducted with insect pre-microRNA (pre-miR) transcripts that were modified to contain microRNAs targeted to insect genes and expressed in transgenic Nicotiana benthamiana plants. These modified pre-miRs remained largely unprocessed in plants. Thus, the insect pest H. armigera, when fed on the leaves of these plants, had a significant increase in mortality, developmental abnormalities, and delays in growth rates (Bally et al., 2020).

piRNAs that were identified for the first time in D. melanogaster, are single-stranded noncoding RNAs that can initiate epigenetic events within insect genomes (Glastad et al., 2019). They interact with transcribed genes inducing co-transcriptional silencing and generating heterochromatic marks where transposable elements are present, thus protecting the genome from damages the transposable elements could bring (Glastad et al., 2019).

lncRNAs are particularly suggested to be involved in caste development in Hymenoptera. In this insect group, lncRNA regulates the size of the worker ovaries in honeybees (Humann et al., 2013; Richard et al., 2021), binds to specific targets, and recruits chromatin-modifying enzymes, initiating the formation of a silent or an active chromatin site (Glastad et al., 2019).

3. Valproic Acid Effects on Epigenetic Markers

Some drugs may affect the epigenetic information by acting on the deposition or removal of epigenetic markers. One of these drugs is valproic acid which may work through different metabolic pathways, affecting several types of epigenetic markers and behaving as an epigenetic modulator.

Valproic acid is a short-chain fatty acid that in association with its sodium salt (VPA) has been widely prescribed as an anticonvulsive drug. The effects of VPA involved with the treatment of seizure disorders revealed activities as inhibition of transamination of the neurotransmitter gamma-aminobutyric acid (GABA) and blockage of the voltage-gated sodium and T-type calcium channels (Chateauvieux et al., 2010). VPA has also been demonstrated to have a binding affinity for chromatin components by acting directly on histones and DNA (Sargolzaei et al., 2017; Vidal and Mello, 2020, 2022) and altering histone H1/nucleosome ratios (Baumann et al., 2021).

In addition to these pharmacological effects, VPA has been found to inhibit cell proliferation, affecting mitotic indices and eliciting cell death pathways, especially in tumor cells. These findings allowed it to be proposed alone or synergistically combined with other drugs as a promising antitumor agent that has been evaluated under phase I and II clinical trials (Duenas-Gonzalez et al., 2008; Mohammed et al., 2011; Goyal and Rodriguez, 2013; Heers et al., 2018; Zhang et al., 2019). Although many advantageous effects have been demonstrated for the use of VPA, it is not to be neglected that some adverse effects like hepatotoxicity, teratogenesis, and expansion of leukemic stem cell population are risks that limit its use in humans (Bug et al., 2007; Lennartsson and Ekwall, 2009; Chateauvieux et al., 2010).

VPA was also demonstrated as a potent drug that affects epigenetic markers in a vast number of human and animal cells, changing gene expression and chromatin interaction with regulatory factors. Among these effects, inhibition of class I HDAC, with the activation of diverse gene promoters, and promoting chromatin remodeling was soon revealed (Göttlicher et al., 2001; Phiel et al., 2001; Eyal et al., 2004; Felisbino et al., 2011; Mello, 2021). In rats, many genes involved in epileptogenesis were demonstrated to become upregulated when hyperacetylation of histones on their promoters was induced by VPA (Fukuchi et al., 2009). A higher number of differentially expressed genes can result from the VPA action, as demonstrated, for instance, in HeLa cells (Dejligbjerg et al., 2008) and, under a hyperglycemic microenvironment, in HepG2 cells (Felisbino et al., 2021).

The methylation status of histones and DNA is also affected by the VPA action in many cell types. Methylation and demethylation of histones especially affecting lysine residues are events modulated by the VPA action that may occur simultaneously with HDAC inhibition (Ganai et al., 2015), affecting the intensification of global gene expression and depending on the metabolized residues (Lanouette et al., 2014; Mello, 2021). DNA demethylation promoted by VPA is a complex process that generally stands longer than histone acetylation (Detich et al., 2003; Lee et al., 2010; Perisic et al., 2010). It flows through a passive or an active pathway, depending on the cell type, and is especially verified to affect tumor suppressor genes (Milutinovic et al., 2007; Gu et al., 2012; Veronezi et al., 2017). The passive pathway presumes suppression of the activity of enzymes of the DNMT family that are responsible for the maintenance of the methylation status in cytosines. The active pathway of DNA demethylation involves the action of enzymes of the ten-eleven-translocation (TET) family that converts 5mC into C derivatives (Guo et al., 2011; Wu and Zhang, 2014; Rocha et al., 2019). There are cells in which, although acting predominantly within an active pathway, the DNA demethylation phenomenon induced by VPA may also occur within a passive pathway (Rocha et al., 2019).

4. VPA Effects in Insects

The use of mammals in scientific activities has provoked considerable discussions over the years regarding the ethical character, mainly due to the use of a high number of animals and the suffering caused in various scientific procedures (Liguori et al., 2017; Santos, 2019). Insects have been proposed as an alternative for analysis of potential epigenetic side effects, including those transferable to offspring, on account of their shorter generation intervals, high fecundity, facilities for using larger samples, and resistance to pathogens, parasites, and environmental stress, thus diminishing ethical concerns (Mukherjee et al., 2015; Bingsohn et al., 2016). Furthermore, insects present themselves as remarkable and important models for the research of epigenetic inheritance, since many insect species show high phenotypic plasticity, that is, the ability of an individual organism to respond to the environment by producing alternative phenotypes based on the same genotype (Manfredini et al., 2019). Epigenetic research on insects is an important tool for studying biodiversity, as environmental stimuli result in heritable phenotypic changes with biological variation without mutations and independent alterations in the DNA sequence to the detriment of variation in gene expression levels (Amiri, 2019).

A few experimental studies using VPA have been undertaken in insects. Among these, some are proposed as alternative models for epigenetic researches while others are devoted to search for effects on precise epigenetic markers and action mechanisms or involve the determination of toxicity induction.

MJDtr-Q78 transgenic Drosophila specimens have been revealed as a strategic model for studies addressed to a VPA treatment of a human disorder known as Machado-Joseph Disease (MJD), which is a polyglutamine (polyQ) neurodegenerative disorder and that involves an imbalance in histone acetylation (Yi et al., 2013). This transgenic model exhibits neurodegenerative phenotypes that could be considered similar to characteristics of the human disease. Using this model, VPA treatment was found to alleviate neurodegeneration, suppressing apoptosis and restoring the imbalance in the acetylation levels of histones H3 and H4 (Yi et al., 2013). At a dose of 2.5 mM for 15 days VPA prevented eye depigmentation while a dose-dependent increase in climbing activity was verified for flies under gentler VPA doses (< 1.5 mM for 5 days). Life span was mildly prolonged under a 0.5 mM VPA treatment. Based on these data, VPA was suggested as a possible therapeutic drug in the MJD disease, suppressing retinal cell death via an anti-apoptosis pathway (Yi et al., 2013).

Drosophila has also been considered an attractive system to unravel potential pathway mechanisms of anti-epilepsy drugs, including VPA, in the treatment of several other neurological disorders, revealing differential expression of only a small number of genes (Singh et al., 2011). As concerned with the modulation of bipolar disorder using the Drosophila model, VPA has been found to induce transcriptional responses at gene ontology and pathway level with similar ontology as lithium (Herteleer et al., 2016). Using Drosophila culture cells and adult flies, it was demonstrated that VPA and lithium affect significantly overlapping genes similar to the effects described for mammals, showing that these drugs act on evolutionarily conserved pathways (Herteleer et al., 2016).

When screened for the VPA action, the beetle T. castaneum has been revealed to experience a longer-lasting effect than vertebrates. In this model, VPA induces delayed development, reduced longevity, declined fertility, and fecundity and revealed a warning system for transgenerational epigenetic side effects (Bingsohn et al., 2016).

A positive longevity effect was reported for A. mellifera under treatment with VPA (Rasmussen et al., 2021). Because this insect is reported to contain a functional DNA methylation system similar to humans, Rasmussen et al. (2021) investigated whether DNA global methylation changes induced by VPA occurred along with the insect lifespan. The fact that they did not detect significant effects on this level may have been due to the use of ELISA assay for such investigation, which was not effective enough to detect response changes at specific genome sites.

In Malpighian tubules of T. infestans injected with 0.5 mM VPA or cultivated in vitro in presence of 0.05 mM VPA for 4 h, a few cells showed decondensation of the heterochromatin bodies that constitute chromocenters (Alvarenga et al., 2016; Bassani et al., 2021). It is interesting that although this VPA-induced heterochromatin imaging change affected only a few cells, this event could not be associated with induction of H3K9 acetylation or DNA demethylation (Alvarenga et al., 2016; Bassani et al., 2021). Other epigenetic markers are thus possibly involved with this response, including non-histone proteins that may associate with histone demethylation, which certainly requires further studies (Bassani et al., 2021). Much longer exposition to VPA or the use of more concentrated doses of VPA leads Malpighian tubule cells to apoptosis and necrosis (Bassani et al., 2021). Regarding the response of the euchromatin of these cells to VPA treatment as assessed by H3K9ac immunofluorescence signals, it was slightly intensified under cultivation of the Malpighian tubules in the presence of 0.5 or 1.0 mM VPA for 4 h especially around the chromocenters, a nuclear area previously demonstrated to contain 18S rDNA (Imperador et al., 2020).

In terms of methodological approaches for studies on the VPA action in insects, injection rather than drug-feeding methods has been preferred to ameliorate seizure-sensitive phenotypes in several mutant genotypes of Drosophila (Howlett and Tanouye, 2013). In T. castaneum and A. mellifera, VPA has been furnished as a supplement on diet (Bingsohn et al., 2016; Rasmussen et al., 2021). In T. infestans, both injection and tissue culture revealed efficient to search for epigenetic changes following VPA treatment (Alvarenga et al., 2016; Bassani et al., 2021).

5. Conclusion

Epigenetics has gained significant attention from the scientific audience as it explains changes in gene expression without the modification in the genetic code of animal and plant species. Progress in this matter has been benefited from the use of drugs that act as epigenetic modulators. However, although Waddington’s pioneering epigenetic studies initially referred to an insect (D. melanogaster) (Waddington, 2012), the investigation of epigenetic markers, interpretation of epigenetic mechanisms and use as alternative models for revealing responses to epigenetic modulators in another insect species is relatively recent. VPA, a drug widely prescribed for the treatment of neurological disorders as well as a promising antitumor agent and a potent epigenetic modulator may reveal as an interesting candidate for unravel new pathway mechanisms of drug effects, including those of pharmacological interest, when administered to insects. Using insects to evaluate VPA actions may allow tracking effects on complex fitness parameters and the expression of epigenetic regulatory genes, being a valuable early warning system for epigenetic risk factors that otherwise would be difficult to detect in mammals (Bingsohn et al., 2016). Many investigations that will bring new knowledge and possibly unexpected new information would certainly be developed and reported in forthcoming years.

Acknowledgements

This research was supported by the São Paulo State Research Foundation (FAPESP, Brazil; grants no. 2015/10356-2, 2018/07888-0) and the Brazilian National Council for Research and Development (CNPq, grant no. 421299/2018-5). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. D.S.S. received a fellowship from FAPESP (grant no. 2019/20833-3). M.A.R. was recipient of a fellowship from the Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES, Brazil, code 001). M.L.S.M. received a fellowship from CNPq (grant no. 304797/2019-7).

References

• AGRAWAL, A., RAJAMANI, V., REDDY, V.S., MUKHERJEE, S.K. and BHATNAGAR, R.K., 2015. Transgenic plants over-expressing insect-specific microRNA acquire insecticidal activity against Helicoverpa armigera: an alternative to Bt-toxin technology. Transgenic Research, vol. 24, no. 5, pp. 791-801. http://dx.doi.org/10.1007/s11248-015-9880-x PMid:25947089.
  » http://dx.doi.org/10.1007/s11248-015-9880-x
• ALVARENGA, E.M., IMPERADOR, C.H.L., BARDELLA, V.B., RODRIGUES, V.L.C.C., MONDIN, M., CABRAL-DE-MELLO, D.C., MORAES, A.S. and MELLO, M.L.S., 2018. Histone acetylation and methylation marks in chromatin of Panstrongylus megistus (Hemiptera, Reduviidae). Acta Histochemica, vol. 120, no. 6, pp. 572-577. http://dx.doi.org/10.1016/j.acthis.2018.07.002 PMid:30005894.
  » http://dx.doi.org/10.1016/j.acthis.2018.07.002
• ALVARENGA, E.M., MONDIN, M., MARTINS, J.A., RODRIGUES, V.L.C.C., VIDAL, B.C., RINCONES, J., CARAZZOLLE, M., ANDRADE, L.M. and MELLO, M.L.S., 2011. Spatial distribution of AT- and GC-rich DNA within interphase cell nuclei of Triatoma infestans Klug. Micron, vol. 42, no. 6, pp. 568-578. http://dx.doi.org/10.1016/j.micron.2011.02.002 PMid:21382722.
  » http://dx.doi.org/10.1016/j.micron.2011.02.002
• ALVARENGA, E.M., RODRIGUES, V.L.C.C., MORAES, A.S., NAVES, L.S., MONDIN, M., FELISBINO, M.B. and MELLO, M.L.S., 2016. Histone epigenetic marks in heterochromatin and euchromatin of the Chagas’ disease vector, Triatoma infestans. Acta Histochemica, vol. 118, no. 4, pp. 401-412. http://dx.doi.org/10.1016/j.acthis.2016.04.002 PMid:27079857.
  » http://dx.doi.org/10.1016/j.acthis.2016.04.002
• AMIRI, A., 2019. Epigenetic in insects. Journal of Epigenetics, vol. 1, pp. 35-42.
• ARAUJO, N.S. and ARIAS, M.C., 2021. Gene expression and epigenetics reveal species-specific mechanisms acting upon common molecular pathways in the evolution of task division in bees. Scientific Reports, vol. 11, no. 1, p. 3654. http://dx.doi.org/10.1038/s41598-020-75432-8 PMid:33574391.
  » http://dx.doi.org/10.1038/s41598-020-75432-8
• ASGARI, S., 2018. microRNAs as regulators of insect-host-pathogen interactions and immunity. Advances in Insect Physiology, vol. 55, pp. 19-42. http://dx.doi.org/10.1016/bs.aiip.2018.07.004
  » http://dx.doi.org/10.1016/bs.aiip.2018.07.004
• BAIN, S.A., MARSHALL, H., FILIA, A.G., LAETSCH, D.R., HUSNIK, F. and ROSS, L., 2021. Sex-specific expression and DNA methylation in a species with extreme sexual dimorphism and paternal genome elimination. Molecular Ecology, vol. 30, no. 22, pp. 5687-5703. http://dx.doi.org/10.1111/mec.15842 PMid:33629415.
  » http://dx.doi.org/10.1111/mec.15842
• BALLY, J., FISHILEVICH, E., DORAN, R.L., LEE, K., CAMPOS, S.B., GERMAN, M.A., NARVA, K.E. and WATERHOUSE, P.M., 2020. Plin-amiR, a pre-microRNA-based technology for controlling herbivorous insect pests. Plant Biotechnology Journal, vol. 18, no. 9, pp. 1925-1932. http://dx.doi.org/10.1111/pbi.13352 PMid:32012433.
  » http://dx.doi.org/10.1111/pbi.13352
• BARTEL, D.P., 2009. MicroRNAs: target recognition and regulatory functions. Cell, vol. 136, no. 2, pp. 215-233. http://dx.doi.org/10.1016/j.cell.2009.01.002 PMid:19167326.
  » http://dx.doi.org/10.1016/j.cell.2009.01.002
• BASSANI, A., ROCHA, M.A., RODRIGUES, V.L.C.C., SANTOS, D.S., NASCIMENTO, J.D., ROSA, J.A. and MELLO, M.L.S., 2021. Effects of sodium valproate on the chromatin of Triatoma infestans (Klug, 1834) (Hemiptera, Reduviidae) under in vitro culture conditions. Acta Histochemica, vol. 123, no. 3, p. 151695. http://dx.doi.org/10.1016/j.acthis.2021.151695 PMid:33571696.
  » http://dx.doi.org/10.1016/j.acthis.2021.151695
• BAUMANN, C., ZHANG, X., ZHU, L., FAN, Y. and FUENTE, R., 2021. Changes in chromatin accessibility landscape and histone H3 core acetylation during valproic acid-induced differentiation of embryonic stem cells. Epigenetics & Chromatin, vol. 14, no. 1, p. 58. http://dx.doi.org/10.1186/s13072-021-00432-5 PMid:34955095.
  » http://dx.doi.org/10.1186/s13072-021-00432-5
• BEWICK, A.J., VOGEL, K.J., MOORE, A.J. and SCHMITZ, R.J., 2017. Evolution of DNA methylation across insects. Molecular Biology and Evolution, vol. 34, no. 3, pp. 654-665. PMid:28025279.
• BINGSOHN, L., KNORR, E. and VILCINSKAS, A., 2016. The model beetle Tribolium castaneum can be used as an early warning system for transgenerational epigenetic side effects caused by pharmaceuticals. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, vol. 185-186, pp. 57-64. http://dx.doi.org/10.1016/j.cbpc.2016.03.002 PMid:26972758.
  » http://dx.doi.org/10.1016/j.cbpc.2016.03.002
• BLACK, J.C. and WHETSTINE, J.R., 2011. Chromatin landscape: methylation beyond transcription. Epigenetics, vol. 6, no. 1, pp. 9-15. http://dx.doi.org/10.4161/epi.6.1.13331 PMid:20855937.
  » http://dx.doi.org/10.4161/epi.6.1.13331
• BONASIO, R., 2014. The role of chromatin and epigenetics in the polyphenisms of ant castes. Briefings in Functional Genomics, vol. 13, no. 3, pp. 235-245. http://dx.doi.org/10.1093/bfgp/elt056 PMid:24462993.
  » http://dx.doi.org/10.1093/bfgp/elt056
• BUG, G., SCHWARZ, K., SCHOCH, C., KAMPFMANN, M., HENSCHLER, R., HOELZER, D., OTTMANN, O.G. and RUTHARDT, M., 2007. Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia. Haematologica, vol. 92, no. 4, pp. 542-545. http://dx.doi.org/10.3324/haematol.10758 PMid:17488665.
  » http://dx.doi.org/10.3324/haematol.10758
• CHAMBEYRON, S. and SEITZ, H., 2014. Insect small non-coding RNA involved in epigenetic regulations. Current Opinion in Insect Science, vol. 1, pp. 1-9. http://dx.doi.org/10.1016/j.cois.2014.05.001 PMid:32846724.
  » http://dx.doi.org/10.1016/j.cois.2014.05.001
• CHATEAUVIEUX, S., MORCEAU, F., DICATO, M. and DIEDERICH, M., 2010. Molecular and therapeutic potential and toxicity of valproic acid. Journal of Biomedicine & Biotechnology, vol. 2010, p. 479364. http://dx.doi.org/10.1155/2010/479364 PMid:20798865.
  » http://dx.doi.org/10.1155/2010/479364
• CHEN, K., LUAN, X., LIU, Q., WANG, J., CHANG, X., SNIJDERS, A.M., MAO, J.H., SECOMBE, J., DAN, Z., CHEN, J.H., WANG, Z., DONG, X., QIU, C., CHANG, X., ZHANG, D., CELNIKER, S.E. and LIU, X., 2019. Drosophila histone demethylase KDM5 regulates social behavior through immune control and gut microbiota maintenance. Cell Host & Microbe, vol. 25, no. 4, pp. 537-552. http://dx.doi.org/10.1016/j.chom.2019.02.003 PMid:30902578.
  » http://dx.doi.org/10.1016/j.chom.2019.02.003
• DEJLIGBJERG, M., GRAUSLUND, M., LITMAN, T., COLLINS, L., QIAN, X., JEFFERS, M., LICHENSTEIN, H., JENSEN, P.B. and SEHESTED, M., 2008. Differential effects of class I isoform histone deacetylase depletion and enzymatic inhibition by belinostat or valproic acid in HeLa cells. Molecular Cancer, vol. 7, p. 70. http://dx.doi.org/10.1186/1476-4598-7-70 PMid:18789133.
  » http://dx.doi.org/10.1186/1476-4598-7-70
• DETICH, N., BOVENZI, V. and SZYF, M., 2003. Valproate induces replication-independent active DNA demethylation. The Journal of Biological Chemistry, vol. 278, no. 30, pp. 27586-27592. http://dx.doi.org/10.1074/jbc.M303740200 PMid:12748177.
  » http://dx.doi.org/10.1074/jbc.M303740200
• DRELON, C., ROGERS, M.F., BELALCAZAR, H.M. and SECOMBE, J., 2019. The histone demethylase KDM5 controls developmental timing in Drosophila by promoting prothoracic gland endocycles. Development, vol. 146, no. 24, p. dev182568. http://dx.doi.org/10.1242/dev.182568 PMid:31862793.
  » http://dx.doi.org/10.1242/dev.182568
• DUENAS-GONZALEZ, A., CANDELARIA, M., PEREZ-PLASCENCIA, C., PEREZ-CARDENAS, E., CRUZ-HERNANDEZ, E. and HERRERA, L.A., 2008. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. Cancer Treatment Reviews, vol. 34, no. 3, pp. 206-222. http://dx.doi.org/10.1016/j.ctrv.2007.11.003 PMid:18226465.
  » http://dx.doi.org/10.1016/j.ctrv.2007.11.003
• EYAL, S., YAGEN, B., SOBOL, E., ALTSCHULER, Y., SHMUEL, M. and BIALER, M., 2004. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia, vol. 45, no. 7, pp. 737-744. http://dx.doi.org/10.1111/j.0013-9580.2004.00104.x PMid:15230695.
  » http://dx.doi.org/10.1111/j.0013-9580.2004.00104.x
• FELISBINO, M.B., GATTI, M.S.V. and MELLO, M.L.S., 2014. Changes in chromatin structure in NIH 3T3 cells induced by valproic acid and trichostatin A. Journal of Cellular Biochemistry, vol. 115, no. 11, pp. 1937-1947. http://dx.doi.org/10.1002/jcb.24865 PMid:24913611.
  » http://dx.doi.org/10.1002/jcb.24865
• FELISBINO, M.B., TAMASHIRO, W.M.S.C. and MELLO, M.L., 2011. Chromatin remodeling, cell proliferation and cell death in valproic acid-treated HeLa cells. PLoS One, vol. 6, no. 12, p. e29144. http://dx.doi.org/10.1371/journal.pone.0029144 PMid:22206001.
  » http://dx.doi.org/10.1371/journal.pone.0029144
• FELISBINO, M.B., ZIEMANN, M., KHURANA, I., OKABE, J., AL-HASANI, K., MAXWELL, S., HARIKRISHNAN, K.N., OLIVEIRA, C.B.M., MELLO, M.L.S. and EL-OSTA, A., 2021. Valproic acid influences the expression of genes implicated with hyperglycaemia-induced complement and coagulation pathways. Scientific Reports, vol. 11, no. 1, p. 2163. http://dx.doi.org/10.1038/s41598-021-81794-4 PMid:33495488.
  » http://dx.doi.org/10.1038/s41598-021-81794-4
• FUKUCHI, M., NII, T., ISHIMARU, N., MINAMINO, A., HARA, D., TAKASAKI, I., TABUCHI, A. and TSUDA, M., 2009. Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions. Neuroscience Research, vol. 65, no. 1, pp. 35-43. http://dx.doi.org/10.1016/j.neures.2009.05.002 PMid:19463867.
  » http://dx.doi.org/10.1016/j.neures.2009.05.002
• GANAI, S.A., KALLADI, S.M. and MAHADEVAN, V., 2015. HDAC inhibition through valproic acid modulates the methylation profiles in human embryonic kidney cells. Journal of Biomolecular Structure & Dynamics, vol. 33, no. 6, pp. 1185-1197. http://dx.doi.org/10.1080/07391102.2014.938247 PMid:25012937.
  » http://dx.doi.org/10.1080/07391102.2014.938247
• GEORGE, S., GADDELAPATI, S.C. and PALLI, S.R., 2019. Histone deacetylase 1 suppresses Krüppel homolog 1 gene expression and influences juvenile hormone action in Tribolium castaneum. Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 36, pp. 17759-17764. http://dx.doi.org/10.1073/pnas.1909554116 PMid:31439816.
  » http://dx.doi.org/10.1073/pnas.1909554116
• GLASTAD, K.M., HUNT, B.G. and GOODISMAN, M.A.D., 2019. Epigenetics in insects: genome regulation and the generation of phenotypic diversity. Annual Review of Entomology, vol. 64, no. 1, pp. 185-203. http://dx.doi.org/10.1146/annurev-ento-011118-111914 PMid:30285490.
  » http://dx.doi.org/10.1146/annurev-ento-011118-111914
• GODAY, C. and RUIZ, M.F., 2002. Differential acetylation of histones H3 and H4 in paternal and maternal germline chromosomes during development of sciarid flies. Journal of Cell Science, vol. 115, no. 24, pp. 4765-4775. http://dx.doi.org/10.1242/jcs.00172 PMid:12432065.
  » http://dx.doi.org/10.1242/jcs.00172
• GÖTTLICHER, M., MINUCCI, S., ZHU, P., KRÄMER, O.H., SCHIMPF, A., GIAVARA, S., SLEEMAN, J.P., COCO, F.L., NERVI, C., PELICCI, P.G. and HEINZEL, T., 2001. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. The EMBO Journal, vol. 20, no. 24, pp. 6969-6978. http://dx.doi.org/10.1093/emboj/20.24.6969 PMid:11742974.
  » http://dx.doi.org/10.1093/emboj/20.24.6969
• GOYAL, J. and RODRIGUEZ, R., 2013. Evidence from clinical trials for the use of valproic acid in solid tumors: focus on prostate cancer. Clinical Investigation, vol. 3, no. 5, pp. 467-478. http://dx.doi.org/10.4155/cli.13.23
  » http://dx.doi.org/10.4155/cli.13.23
• GU, S., TIAN, Y., CHLENSKI, A., SALWEN, H.R., LU, Z., RAJ, J.U. and YANG, Q., 2012. Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. Anti-Cancer Drugs, vol. 23, no. 10, pp. 1054-1066. http://dx.doi.org/10.1097/CAD.0b013e32835739dd PMid:22863973.
  » http://dx.doi.org/10.1097/CAD.0b013e32835739dd
• GUO, J.U., SU, Y., ZHONG, C., MING, G.L. and SONG, H., 2011. Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell Cycle, vol. 10, no. 16, pp. 2662-2668. http://dx.doi.org/10.4161/cc.10.16.17093 PMid:21811096.
  » http://dx.doi.org/10.4161/cc.10.16.17093
• GUO, S., JIANG, F., YANG, P., LIU, Q., WANG, X. and KANG, L., 2016. Characteristics and expression patterns of histone-modifying enzyme systems in the migratory locust. Insect Biochemistry and Molecular Biology, vol. 76, pp. 18-28. http://dx.doi.org/10.1016/j.ibmb.2016.06.010 PMid:27343382.
  » http://dx.doi.org/10.1016/j.ibmb.2016.06.010
• GUO, X., SU, S., SKOGERBOE, G., DAI, S., LI, W., LI, Z., LIU, F., NI, R., GUO, Y., CHEN, S., ZHANG, S. and CHEN, R., 2013. Recipe for a busy bee: microRNAs in honey bee caste determination. PLoS One, vol. 8, no. 12, p. e81661. http://dx.doi.org/10.1371/journal.pone.0081661 PMid:24349106.
  » http://dx.doi.org/10.1371/journal.pone.0081661
• HEERS, H., STANISLAW, J., HARRELSON, J. and LEE, M.W., 2018. Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer. European Journal of Pharmacology, vol. 835, pp. 61-74. http://dx.doi.org/10.1016/j.ejphar.2018.07.057 PMid:30075223.
  » http://dx.doi.org/10.1016/j.ejphar.2018.07.057
• HERTELEER, L., ZWARTS, L., HENS, K., FORERO, D., DEL-FAVERO, J. and CALLAERTS, P., 2016. Mood stabilizing drugs regulate transcription of immune, neuronal and metabolic pathway genes in Drosophila. Psychopharmacology, vol. 233, no. 9, pp. 1751-1762. http://dx.doi.org/10.1007/s00213-016-4223-z PMid:26852229.
  » http://dx.doi.org/10.1007/s00213-016-4223-z
• HOWLETT, I.C. and TANOUYE, M.A., 2013. Seizure-sensitivity in Drosophila is ameliorated by dorsal vessel injection of the antiepileptic drug valproate. Journal of Neurogenetics, vol. 27, no. 4, pp. 143-150. http://dx.doi.org/10.3109/01677063.2013.817574 PMid:23941042.
  » http://dx.doi.org/10.3109/01677063.2013.817574
• HUMANN, F.C., TIBERIO, G.J. and HARTFELDER, K., 2013. Sequence and expression characteristics of long noncoding RNAs in honey bee caste development – potential novel regulators for transgressive ovary size. PLoS One, vol. 8, no. 10, p. e78915. http://dx.doi.org/10.1371/journal.pone.0078915 PMid:24205350.
  » http://dx.doi.org/10.1371/journal.pone.0078915
• IMPERADOR, C.H.L., BARDELLA, V.B., ANJOS, E.H.M., RODRIGUES, V.L.C.C., CABRAL-DE-MELLO, D.C. and MELLO, M.L.S., 2020. Spatial distribution of heterochromatin bodies in the nuclei of Triatoma infestans (Klug). Microscopy and Microanalysis, vol. 26, no. 3, pp. 567-574. http://dx.doi.org/10.1017/S143192762000149X PMid:32393416.
  » http://dx.doi.org/10.1017/S143192762000149X
• KELLEHER, E.S., 2016. Reexamining the p-element invasion of Drosophila melanogaster through the lens of piRNA silencing. Genetics, vol. 203, no. 4, pp. 1513-1531. http://dx.doi.org/10.1534/genetics.115.184119 PMid:27516614.
  » http://dx.doi.org/10.1534/genetics.115.184119
• KOZERETSKA, I.A., SERGA, S.V., KOLIADA, A.K. and VAISERMAN, A.M., 2017. Epigenetic regulation of longevity in insects. Advances in Insect Physiology, vol. 53, pp. 87-114. http://dx.doi.org/10.1016/bs.aiip.2017.03.001
  » http://dx.doi.org/10.1016/bs.aiip.2017.03.001
• LANOUETTE, S., MONGEON, V., FIGEYS, D. and COUTURE, J.F., 2014. The functional diversity of protein lysine methylation. Molecular Systems Biology, vol. 10, no. 4, p. 724. http://dx.doi.org/10.1002/msb.134974 PMid:24714364.
  » http://dx.doi.org/10.1002/msb.134974
• LEE, J.H., CHOY, M.L., NGO, L., FOSTER, S.S. and MARKS, P.A., 2010. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 33, pp. 14639-14644. http://dx.doi.org/10.1073/pnas.1008522107 PMid:20679231.
  » http://dx.doi.org/10.1073/pnas.1008522107
• LENNARTSSON, A. and EKWALL, K., 2009. Histone modification patterns and epigenetic codes. Biochimica et Biophysica Acta. G, General Subjects, vol. 1790, no. 9, pp. 863-868. http://dx.doi.org/10.1016/j.bbagen.2008.12.006 PMid:19168116.
  » http://dx.doi.org/10.1016/j.bbagen.2008.12.006
• LIGUORI, G.R., JERONIMUS, B.F., LIGUORI, T.T.A., MOREIRA, L.F.P. and HARMSEN, M.C., 2017. Ethical issues in the use of animal models for tissue engineering: reflections on legal aspects, moral theory, three rs strategies, and harm-benefit analysis. Tissue Engineering. Part C, Methods, vol. 23, no. 12, pp. 850-862. http://dx.doi.org/10.1089/ten.tec.2017.0189 PMid:28756735.
  » http://dx.doi.org/10.1089/ten.tec.2017.0189
• LO, N., SIMPSON, S.J. and SWORD, G.A., 2018. Epigenetics and developmental plasticity in orthopteroid insects. Current Opinion in Insect Science, vol. 25, pp. 25-34. http://dx.doi.org/10.1016/j.cois.2017.11.003 PMid:29602359.
  » http://dx.doi.org/10.1016/j.cois.2017.11.003
• LYKO, F., RAMSAHOYE, B.H. and JAENISCH, R., 2000. DNA methylation in Drosophila melanogaster. Nature, vol. 408, no. 6812, pp. 538-540. http://dx.doi.org/10.1038/35046205 PMid:11117732.
  » http://dx.doi.org/10.1038/35046205
• MANDRIOLI, M., AZZONI, P., LOMBARDO, G. and MANICARDI, G.C., 2011. Composition and epigenetic markers of heterochromatin in the aphid Aphis nerii (Hemiptera: aphididae). Cytogenetic and Genome Research, vol. 133, no. 1, pp. 67-77. http://dx.doi.org/10.1159/000323510 PMid:21273762.
  » http://dx.doi.org/10.1159/000323510
• MANFREDINI, F., ARBETMAN, M. and TOTH, A.L., 2019. A potential role for phenotypic plasticity in invasions and declines of social insects. Frontiers in Ecology and Evolution, vol. 7, p. 375. http://dx.doi.org/10.3389/fevo.2019.00375
  » http://dx.doi.org/10.3389/fevo.2019.00375
• MATSUURA, K., 2020. Genomic imprinting and evolution of insect societies. Population Ecology, vol. 62, no. 1, pp. 38-52. http://dx.doi.org/10.1002/1438-390X.12026
  » http://dx.doi.org/10.1002/1438-390X.12026
• MELLO, M.L.S., 2021. Sodium valproate-induced chromatin remodeling. Frontiers in Cell and Developmental Biology, vol. 9, p. 645518. http://dx.doi.org/10.3389/fcell.2021.645518 PMid:33959607.
  » http://dx.doi.org/10.3389/fcell.2021.645518
• MILUTINOVIC, S., D’ALESSIO, A.C., DETICH, N. and SZYF, M., 2007. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis, vol. 28, no. 3, pp. 560-571. http://dx.doi.org/10.1093/carcin/bgl167 PMid:17012225.
  » http://dx.doi.org/10.1093/carcin/bgl167
• MOHAMMED, T.A., HOLEN, K.D., JASKULA-SZTUL, R., MULKERIN, D., LUBNER, S.J., SCHELMAN, W.R., EICKHOFF, J., CHEN, H. and LOCONTE, N.K., 2011. A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. The Oncologist, vol. 16, no. 6, pp. 835-843. http://dx.doi.org/10.1634/theoncologist.2011-0031 PMid:21632454.
  » http://dx.doi.org/10.1634/theoncologist.2011-0031
• MUKHERJEE, K., GRIZANOVA, E., CHERTKOVA, E., LEHMANN, R., DUBOVSKIY, I. and VILCINSKAS, A., 2017. Experimental evolution of resistance against Bacillus thuringiensis in the insect model host Galleria mellonella results in epigenetic modifications. Virulence, vol. 8, no. 8, pp. 1618-1630. http://dx.doi.org/10.1080/21505594.2017.1325975 PMid:28521626.
  » http://dx.doi.org/10.1080/21505594.2017.1325975
• MUKHERJEE, K., TWYMAN, R.M. and VILCINSKAS, A., 2015. Insects as models to study the epigenetic basis of disease. Progress in Biophysics and Molecular Biology, vol. 118, no. 1-2, pp. 69-78. http://dx.doi.org/10.1016/j.pbiomolbio.2015.02.009 PMid:25778758.
  » http://dx.doi.org/10.1016/j.pbiomolbio.2015.02.009
• NEAFSEY, D.E., WATERHOUSE, R.M., ABAI, M.R., AGANEZOV, S.S., ALEKSEYEV, M.A., ALLEN, J.E., AMON, J., ARCÀ, B., ARENSBURGER, P., ARTEMOV, G., ASSOUR, L.A., BASSERI, H., BERLIN, A., BIRREN, B.W., BLANDIN, S.A., BROCKMAN, A.I., BURKOT, T.R., BURT, A., CHAN, C.S., CHAUVE, C., CHIU, J.C., CHRISTENSEN, M., COSTANTINI, C., DAVIDSON, V.L.M., DELIGIANNI, E., DOTTORINI, T., DRITSOU, V., GABRIEL, S.B., GUELBEOGO, W.M., HALL, A.B., HAN, M.V., HLAING, T., HUGHES, D.S., JENKINS, A.M., JIANG, X., JUNGREIS, I., KAKANI, E.G., KAMALI, M., KEMPPAINEN, P., KENNEDY, R.C., KIRMITZOGLOU, I.K., KOEKEMOER, L.L., LABAN, N., LANGRIDGE, N., LAWNICZAK, M.K.N., LIRAKIS, M., LOBO, N.F., LOWY, E., MACCALLUM, R.M., MAO, C., MASLEN, G., MBOGO, C., MCCARTHY, J., MICHEL, K., MITCHELL, S.N., MOORE, W., MURPHY, K.A., NAUMENKO, A.N., NOLAN, T., NOVOA, E.M., O’LOUGHLIN, S., ORINGANJE, C., OSHAGHI, M.A., PAKPOUR, N., PAPATHANOS, P.A., PEERY, A.N., POVELONES, M., PRAKASH, A., PRICE, D.P., RAJARAMAN, A., REIMER, L.J., RINKER, D.C., ROKAS, A., RUSSELL, T.L., SAGNON, N., SHARAKHOVA, M.V., SHEA, T., SIMÃO, F.A., SIMARD, F., SLOTMAN, M.A., SOMBOON, P., STEGNIY, V., STRUCHINER, C.J., THOMAS, G.W.C., TOJO, M., TOPALIS, P., TUBIO, J.M.C., UNGER, M.F., VONTAS, J., WALTON, C., WILDING, C.S., WILLIS, J.H., WU, Y.-C., YAN, G., ZDOBNOV, E.M., ZHOU, X., CATTERUCCIA, F., CHRISTOPHIDES, G.K., COLLINS, F.H., CORNMAN, R.S., CRISANTI, A., DONNELLY, M.J., EMRICH, S.J., FONTAINE, M.C., GELBART, W., HAHN, M.W., HANSEN, I.A., HOWELL, P.I., KAFATOS, F.C., KELLIS, M., LAWSON, D., LOUIS, C., LUCKHART, S., MUSKAVITCH, M.A.T., RIBEIRO, J.M., RIEHLE, M.A., SHARAKHOV, I.V., TU, Z., ZWIEBEL, L.J. and BESANSKY, N.J., 2015. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes. Science, vol. 347, no. 6217, p. 1258522. http://dx.doi.org/10.1126/science.1258522 PMid:25554792.
  » http://dx.doi.org/10.1126/science.1258522
• OLDROYD, B.P. and YAGOUND, B., 2021. The role of epigenetics, particularly DNA methylation, in the evolution of caste in insect societies. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, vol. 376, no. 1826, p. 20200115. http://dx.doi.org/10.1098/rstb.2020.0115 PMid:33866805.
  » http://dx.doi.org/10.1098/rstb.2020.0115
• PERISIC, T., ZIMMERMANN, N., KIRMEIER, T., ASMUS, M., TUORTO, F., UHR, M., HOLSBOER, F., REIN, T. and ZSCHOCKE, J., 2010. Valproate and amitriptyline exert common and divergent influences on global and gene promoter-specific chromatin modifications in rat primary astrocytes. Neuropsychopharmacology, vol. 35, no. 3, pp. 792-805. http://dx.doi.org/10.1038/npp.2009.188 PMid:19924110.
  » http://dx.doi.org/10.1038/npp.2009.188
• PHIEL, C.J., ZHANG, F., HUANG, E.Y., GUENTHER, M.G., LAZAR, M.A. and KLEIN, P.S., 2001. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. The Journal of Biological Chemistry, vol. 276, no. 39, pp. 36734-36741. http://dx.doi.org/10.1074/jbc.M101287200 PMid:11473107.
  » http://dx.doi.org/10.1074/jbc.M101287200
• PROVATARIS, P., MEUSEMANN, K., NIEHUIS, O., GRATH, S. and MISOF, B., 2018. Signatures of DNA methylation across insects suggest reduced DNA methylation levels in holometabola. Genome Biology and Evolution, vol. 10, no. 4, pp. 1185-1197. http://dx.doi.org/10.1093/gbe/evy066 PMid:29697817.
  » http://dx.doi.org/10.1093/gbe/evy066
• RASMUSSEN, E.M.K., SEIER, K.L., PEDERSEN, I.K., KREIBICH, C., AMDAM, G.V., MÜNCH, D. and DAHL, J.A., 2021. Screening bioactive food compounds in honey bees suggests curcumin blocks alcohol-induced damage to longevity and DNA methylation. Scientific Reports, vol. 11, no. 1, p. 19156. http://dx.doi.org/10.1038/s41598-021-98614-4 PMid:34580381.
  » http://dx.doi.org/10.1038/s41598-021-98614-4
• RICHARD, G., JAQUIÉRY, J. and TRIONNAIRE, G.L., 2021. Contribution of epigenetic mechanisms in the regulation of environmentally-induced polyphenism in insects. Insects, vol. 12, no. 7, p. 649. http://dx.doi.org/10.3390/insects12070649 PMid:34357309.
  » http://dx.doi.org/10.3390/insects12070649
• ROCHA, M.A., VERONEZI, G.M.B., FELISBINO, M.B., GATTI, M.S.V., TAMASHIRO, W.M.S.C. and MELLO, M.L.S., 2019. Sodium valproate and 5-aza-2′-deoxycytidine differentially modulate DNA demethylation in G1 phase-arrested and proliferative HeLa cells. Scientific Reports, vol. 9, no. 1, p. 18236. http://dx.doi.org/10.1038/s41598-019-54848-x PMid:31796828.
  » http://dx.doi.org/10.1038/s41598-019-54848-x
• SANTOS, D.S., 2019. Identification of the entomotoxic mechanisms of two natural insecticides in experimental alternative insect model: extract containing Anatoxin-a(s) and Jaburetox Santa Maria: Federal University of Santa Maria, 120 p. PhD Dissertation in Toxicological Biochemistry.
• SARGOLZAEI, J., RABBANI-CHADEGANI, A., MOLLAEI, H. and DEEZAGI, A., 2017. Spectroscopic analysis of the interaction of valproic acid with histone H1 in solution and in chromatin structure. International Journal of Biological Macromolecules, vol. 99, pp. 427-432. http://dx.doi.org/10.1016/j.ijbiomac.2017.02.098 PMid:28263810.
  » http://dx.doi.org/10.1016/j.ijbiomac.2017.02.098
• SCHULZ, N.K.E., WAGNER, C.I., EBELING, J., RADDATZ, G., DIDDENS-DE BUHR, M.F., LYKO, F. and KURTZ, J., 2018. DNMT1 has an essential function despite the absence of CpG DNA methylation in the red flour beetle Tribolium castaneum. Scientific Reports, vol. 8, no. 1, p. 16462. http://dx.doi.org/10.1038/s41598-018-34701-3 PMid:30405203.
  » http://dx.doi.org/10.1038/s41598-018-34701-3
• SHARAKHOV, I.V. and SHARAKHOVA, M.V., 2015. Heterochromatin, histone modifications, and nuclear architecture in disease vectors. Current Opinion in Insect Science, vol. 10, pp. 110-117. http://dx.doi.org/10.1016/j.cois.2015.05.003 PMid:26097808.
  » http://dx.doi.org/10.1016/j.cois.2015.05.003
• SIEBER, K.R., DORMAN, T., NEWELL, N. and YAN, H., 2021. (Epi)Genetic mechanisms underlying the evolutionary success of eusocial insects. Insects, vol. 12, no. 6, p. 498. http://dx.doi.org/10.3390/insects12060498 PMid:34071806.
  » http://dx.doi.org/10.3390/insects12060498
• SINGH, P., MOHAMMAD, F. and SHARMA, A., 2011. Transcriptomic analysis in a Drosophila model identifies previously implicated and novel pathways in the therapeutic mechanism in neuropsychiatric disorders. Frontiers in Neuroscience, vol. 5, no. 161, p. 161. http://dx.doi.org/10.3389/fnins.2011.00161 PMid:21503142.
  » http://dx.doi.org/10.3389/fnins.2011.00161
• SUZUKI, M.M. and BIRD, A., 2008. DNA methylation landscapes: provocative insights from epigenomics. Nature Reviews. Genetics, vol. 9, no. 6, pp. 465-476. http://dx.doi.org/10.1038/nrg2341 PMid:18463664.
  » http://dx.doi.org/10.1038/nrg2341
• SWAMINATHAN, A., GAJAN, A. and PILE, L.A., 2012. Epigenetic regulation of transcription in Drosophila. Frontiers in Bioscience, vol. 17, no. 3, pp. 909-937. http://dx.doi.org/10.2741/3964 PMid:22201781.
  » http://dx.doi.org/10.2741/3964
• TRONICK, E. and HUNTER, R.G., 2016. Waddington, dynamic systems, and epigenetics. Frontiers in Behavioral Neuroscience, vol. 10, p. 107. http://dx.doi.org/10.3389/fnbeh.2016.00107 PMid:27375447.
  » http://dx.doi.org/10.3389/fnbeh.2016.00107
• VERONEZI, G.M.B., FELISBINO, M.B., GATTI, M.S.V., MELLO, M.L.S. and VIDAL, B.C., 2017. DNA methylation changes in valproic acid-treated HeLa cells as assessed by image analysis, immunofluorescence and vibrational microspectroscopy. PLoS One, vol. 12, no. 1, p. e0170740. http://dx.doi.org/10.1371/journal.pone.0170740 PMid:28114349.
  » http://dx.doi.org/10.1371/journal.pone.0170740
• VIDAL, B.C. and MELLO, M.L.S., 2020. Sodium valproate (VPA) interactions with DNA and histones. International Journal of Biological Macromolecules, vol. 163, pp. 219-231. http://dx.doi.org/10.1016/j.ijbiomac.2020.06.265 PMid:32619665.
  » http://dx.doi.org/10.1016/j.ijbiomac.2020.06.265
• VIDAL, B.C. and MELLO, M.L.S., 2022. Data on FTIR spectra of mixtures of sodium valproate (VPA) and histones H1 and H3. Latin American Data Science, vol. 1, no. 3, pp. 102-109. http://dx.doi.org/10.53805/lads.v1i3.36
  » http://dx.doi.org/10.53805/lads.v1i3.36
• VILLAGRA, C. and FRÍAS-LASSERRE, D., 2020. Epigenetic molecular mechanisms in insects. Neotropical Entomology, vol. 49, no. 5, pp. 615-642. http://dx.doi.org/10.1007/s13744-020-00777-8 PMid:32514997.
  » http://dx.doi.org/10.1007/s13744-020-00777-8
• WADDINGTON, C.H., 2012. The epigenotype. International Journal of Epidemiology, vol. 41, no. 1, pp. 10-13. http://dx.doi.org/10.1093/ije/dyr184 PMid:22186258.
  » http://dx.doi.org/10.1093/ije/dyr184
• WANG, H., LIU, Z., WANG, Y., MA, L., ZHANG, W. and XU, B., 2020. Genome-wide differential DNA methylation in reproductive, morphological, and visual system differences between queen bee and worker bee (Apis mellifera). Frontiers in Genetics, vol. 11, p. 770. http://dx.doi.org/10.3389/fgene.2020.00770 PMid:32903639.
  » http://dx.doi.org/10.3389/fgene.2020.00770
• WANG, W., WANG, X., LI, X., PU, Q., LUO, C., XU, L., PENG, X. and LIU, S., 2019. Genetic manipulation of microRNAs in the silk gland of silkworm, Bombyx mori. Biological Procedures Online, vol. 21, no. 1, p. 16. http://dx.doi.org/10.1186/s12575-019-0102-4 PMid:31427900.
  » http://dx.doi.org/10.1186/s12575-019-0102-4
• WANG, Y., JIANG, F., WANG, H., SONG, T., WEI, Y., YANG, M., ZHANG, J. and KANG, L., 2015. Evidence for the expression of abundant microRNAs in the locust genome. Scientific Reports, vol. 5, no. 1, p. 13608. http://dx.doi.org/10.1038/srep13608 PMid:26329925.
  » http://dx.doi.org/10.1038/srep13608
• WU, C.-T. and MORRIS, J.R., 2001. Genes, genetics, and epigenetics: a correspondence. Science, vol. 293, no. 5532, pp. 1103-1105. http://dx.doi.org/10.1126/science.293.5532.1103 PMid:11498582.
  » http://dx.doi.org/10.1126/science.293.5532.1103
• WU, H. and ZHANG, Y., 2014. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell, vol. 156, no. 1-2, pp. 45-68. http://dx.doi.org/10.1016/j.cell.2013.12.019 PMid:24439369.
  » http://dx.doi.org/10.1016/j.cell.2013.12.019
• YAN, H., BONASIO, R., SIMOLA, D.F., LIEBIG, J., BERGER, S.L. and REINBERG, D., 2015. DNA methylation in social insects: how epigenetics can control behavior and longevity. Annual Review of Entomology, vol. 60, pp. 435-452. http://dx.doi.org/10.1146/annurev-ento-010814-020803 PMid:25341091.
  » http://dx.doi.org/10.1146/annurev-ento-010814-020803
• YI, J., ZHANG, L., TANG, B., HAN, W., ZHOU, Y., CHEN, Z., JIA, D. and JIANG, H., 2013. Sodium valproate alleviates neurodegeneration in SCA3/MJD via suppressing apoptosis and rescuing the hypoacetylation levels of histone H3 and H4. PLoS One, vol. 8, no. 1, p. e54792. http://dx.doi.org/10.1371/journal.pone.0054792 PMid:23382971.
  » http://dx.doi.org/10.1371/journal.pone.0054792
• YOGINDRAN, S. and RAJAM, M.V., 2021. Host-derived artificial miRNA-mediated silencing of ecdysone receptor gene provides enhanced resistance to Helicoverpa armigera in tomato. Genomics, vol. 113, no. 1-Pt 2, pp. 736-747. http://dx.doi.org/10.1016/j.ygeno.2020.10.004 PMid:33058987.
  » http://dx.doi.org/10.1016/j.ygeno.2020.10.004
• ZHANG, Y., ZHANG, Y., LI, M., MENG, F., YU, Z., CHEN, Y. and CUI, G., 2019. Combination of SB431542, CHIR99021 and PD0325901 has a synergic effect on abrogating valproic acid induced epithelial mesenchymal transition and stemness in HeLa, 5637 and SCC 15 cells. Oncology Reports, vol. 41, no. 6, pp. 3545-3554. http://dx.doi.org/10.3892/or.2019.7088 PMid:30942451.
  » http://dx.doi.org/10.3892/or.2019.7088

Publication Dates

• Publication in this collection
  08 Apr 2022
• Date of issue
  2024

History

• Received
  03 Sept 2021
• Accepted
  10 Mar 2022