Moreover, this enzyme affects chromatin condensation simply by regulating histone appearance as well as the known level and activity of some histone modifying enzymes, e.g., it inhibits Suv39h1 methyltransferase degradation and enhances it is activity. in outcome, altered gene appearance. With age, the known degree of heterochromatin reduces, and much less condensed chromatin is certainly more susceptible to DNA harm. On the main one hand, some gene promoters are often designed for the transcriptional machinery; on the other hand, some genes are more protected (locally increased level of heterochromatin). The structure of chromatin is precisely regulated by the epigenetic modification of DNA and posttranslational modification of histones. The methylation of DNA inhibits transcription, histone methylation mostly leads to a more condensed chromatin structure (with some exceptions) and acetylation plays an opposing role. The modification of both DNA and histones is regulated by factors present in the diet. This means that compounds contained in daily food can alter gene expression and protect cells from senescence, and therefore protect the organism from ageing. An opinion prevailed for some time that compounds from the diet do not act through direct regulation of the processes in the organism but through modification of the physiology of the microbiome. In this review we try to explain the role of some food compounds, which by acting on the epigenetic level might protect the organism from age-related diseases and slow down ageing. We also try to shed some light on the role of microbiome in this process. have been identified [78]. Three of them are classic methyltransferases (to DNA methylation. Khalil et al. show that the activity of DNMT2 in aged mouse macrophages is considerably increased, which leads to hypermethylation in promoter regions of autophagy genes and is shown to be upregulated in replicatively senescent human fibroblasts, which suggests its role in longevity regulation. Interestingly, silencing of DNMT2 results in changes in proliferation-related and tumor suppressor miRNAs level and leads to proliferation inhibition and induction of cellular senescence mediated by oxidative stress [83]. silencing in mouse fibroblasts leads to, inter alia, telomere shortening, elevation of cell cycle inhibitors and DNA damage, resulting cell senescence [84]. It is believed that DNA demethylation is not only a passive process occurring as a result of the lack of DNMT1 but can be achieved by active demethylation [19]. The methylated cytosine is oxidized to 5-hydroxymethylcytosine (5hmC) by the ten-eleven translocation (TET) enzymes consisting of three family members, i.e., TET1, TET2 and TET3 [85]. These proteins can catalyze further 5hmC oxidation to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), that usually ends up with the removal of the modified base by base excision repair or decarboxylation [86]. How the process of DNA demethylation proceeds in vivo, however, is still under extensive investigation. Nevertheless, different tissues seem to accumulate 5hmC at varying levels [87,88], and the enrichment is usually observed at promoters of specific genes [89]. This indicates, that 5hmC does not only serve as an intermediate in the active DNA demethylation but can also stand as an epigenetic regulatory mark controlling gene expression. The 5hmC is most abundant in embryonic stem cells, adult somatic stem cells and brain tissue [88,89] although localization of the 5hmC-enriched regions depends on the type of cell and developmental stage. Profound changes are found in ageing mouse brains; a study revealed a global increase in hippocampal 5hmc content, which was unrelated to oxidative stress [90]. The same trend was noted in substantia nigra, where the increase of 5hmC was observed in contrast to striatum which has stable DNA methylation status across ageing [91]. Moreover, chromatin accessibility is regulated via a crosstalk between DNA methylation and histone modifications. Methylated DNA recruits histone deacetylases and histone methyltransferases e.g., SuV39H1 which, by methylating H3K9 (histone H3 lysine 9), tightens the chromatin structure [19]. Moreover, HP-1 (heterochromatin protein 1) is responsible for recruitment of DNA methyltransferases, DNMTs [92]. 3.2. Posttranslational Modification of Histones The next level of nuclear organization and gene expression control concerns chromatin structure predominantly controlled by posttranslational modifications (PTMs) of histones. Nrf2-IN-1 Histones are highly conserved DNA-binding proteins, that form a nucleosome core. Each nucleosome consists of two copies of canonical histones H2A, H2B, H3 and H4. The double stranded DNA is wound on the established histone octamer and the whole complex is stabilized by linker histone H1 [93]. Each core histone (except for H4) has variants which differ in amino acid sequence and can be synthesized independently of DNA replication both in mitotic and post-mitotic cells [94]. The incorporation of histone variants certainly adds up to the complexity of the nucleosome organization and gene expression control. Histones can be post-translationally modified on the N-terminal tails protruding from the globular histone core. Depending on the type of modification the impact on chromatin accessibility and stability differs considerably. Among the plethora of PTMs the most prevalent are methylation, acetylation, Rabbit polyclonal to ACSF3 phosphorylation and ubiquitination [95]. These modifications are precisely controlled by highly specialized writers, erasers and readers, that incorporate, remove and recognize PTMs in.For example, senescent human fibroblasts show relatively elevated levels of H4K16ac in gene promoters. (locally increased level of heterochromatin). The structure of chromatin is precisely regulated by the epigenetic modification of DNA and posttranslational modification of histones. The methylation of DNA inhibits transcription, histone methylation mostly leads to a more condensed chromatin structure (with some exceptions) and acetylation plays an opposing role. The modification of both DNA and histones is regulated by factors present in the diet. This means that compounds contained in daily food can alter gene expression and protect cells from senescence, and therefore protect the organism from ageing. An opinion prevailed for some time that compounds from the diet do not act through direct regulation of the processes in the organism but through modification of the physiology of the microbiome. In this review we try to explain the role of some food compounds, which by acting on the epigenetic level might protect the organism from age-related diseases and slow down ageing. We also try to shed some light on the role of microbiome in this process. have been identified [78]. Three of them are classic methyltransferases (to DNA methylation. Khalil et al. show that the activity of DNMT2 in aged mouse macrophages is considerably increased, which leads to hypermethylation in Nrf2-IN-1 promoter regions of autophagy genes and is shown to be upregulated in replicatively senescent human fibroblasts, which suggests its role in longevity regulation. Interestingly, silencing of DNMT2 results in changes in proliferation-related and tumor suppressor miRNAs level and leads to proliferation inhibition and induction of cellular senescence mediated by oxidative stress [83]. silencing in mouse fibroblasts leads to, inter alia, telomere shortening, elevation of cell cycle inhibitors and DNA damage, resulting cell senescence [84]. It is believed that DNA demethylation is not only a passive process occurring as a result of the lack of DNMT1 but can be achieved by active demethylation [19]. The methylated cytosine is oxidized to 5-hydroxymethylcytosine (5hmC) by the ten-eleven translocation (TET) enzymes consisting of three family members, i.e., TET1, TET2 and TET3 [85]. These protein can catalyze additional 5hmC oxidation to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), that always eventually ends up with removing the improved base by bottom excision fix or decarboxylation [86]. The way the procedure for DNA demethylation proceeds in vivo, nevertheless, continues to be under extensive analysis. Nevertheless, different tissue appear to accumulate 5hmC at differing amounts [87,88], as well as the enrichment is normally noticed at promoters of particular Nrf2-IN-1 genes [89]. This means that, that 5hmC will not just serve as an intermediate in the energetic DNA demethylation but may also stand as an epigenetic regulatory tag controlling gene appearance. The 5hmC is normally most loaded in embryonic stem cells, adult somatic stem cells and human brain tissues [88,89] although localization from the 5hmC-enriched locations depends on the sort of cell and developmental stage. Profound adjustments are located in ageing mouse brains; a report revealed a worldwide upsurge in hippocampal 5hmc articles, that was unrelated to oxidative tension [90]. The same development was observed in substantia nigra, where in fact the boost of 5hmC was seen in comparison to striatum which includes steady DNA methylation position across ageing [91]. Furthermore, chromatin ease of access is regulated with a crosstalk between DNA methylation and Nrf2-IN-1 histone adjustments. Methylated DNA recruits histone deacetylases and histone methyltransferases e.g., SuV39H1 which, by methylating H3K9 (histone H3 lysine 9), tightens the chromatin framework [19]. Moreover, Horsepower-1 (heterochromatin proteins 1) is in charge of recruitment of DNA methyltransferases, DNMTs [92]. 3.2. Posttranslational Adjustment of Histones Another degree of nuclear company and gene appearance control problems chromatin framework predominantly managed by posttranslational adjustments (PTMs) of histones. Histones are extremely conserved DNA-binding protein, that type a nucleosome primary. Each nucleosome includes two copies of canonical histones H2A, H2B, H3 and H4. The dual stranded DNA is normally wound over the set up histone octamer and the complete complex is normally stabilized by linker histone H1 [93]. Each primary histone (aside from H4) has variations which differ in amino acidity sequence and will be synthesized separately of DNA replication both in mitotic and post-mitotic cells [94]. The incorporation of histone variations certainly results in the complexity from the nucleosome company and gene appearance control. Histones could be post-translationally improved over the N-terminal tails protruding in the globular histone primary. With regards to the type of adjustment the effect on chromatin ease of access and balance differs significantly. Among the variety of PTMs one of the most widespread are methylation, acetylation, phosphorylation and ubiquitination [95]. These adjustments are precisely managed by highly specific authors, erasers and visitors, that incorporate, remove and.