V posledných desaťročiach sme zaznamenali výrazný nárast počtu cisárskych rezov. Hoci je pôrod cisárskym rezom život zachraňujúci, je spojený so zvýšeným rizikom nepriaznivých zdravotných následkov u novorodencov, vrátane respiračných a atopických ochorení, obezity, cukrovky a závažných autoimunitných ochorení. Presné mechanizmy, ktoré sú základom týchto spojitostí zostávajú nepochopené; epigenetické modifikácie sa však ukázali ako pravdepodobný molekulárny základ spájajúci perinatálne faktory s budúcou náchylnosťou na ochorenie. Tento prehľad spája súčasnú literatúru a odhaľuje, že spôsob pôrodu môže ovplyvniť epigenetické markery u novorodencov, predovšetkým prostredníctvom zmien globálnej metylácie DNA a génovo špecifických metylačných vzorcov.
Recent decades have seen a notable increase in cesarean section rates. Although lifesaving, cesarean delivery is associated with an elevated risk of adverse health outcomes in newborns, including respiratory diseases, atopic disorders, obesity, diabetes, and severe autoimmune conditions. The exact mechanisms underlying these associations remain elusive; however, epigenetic modifications have emerged as a plausible molecular basis linking perinatal factors with future disease susceptibility. This review summarizes current literature, revealing that the delivery method may influence epigenetic markers in neonates, primarily through alterations in global DNA methylation and gene-specific methylation patterns.
BACKGROUND: Obesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. METHODS: We analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches. RESULTS: Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner. CONCLUSIONS: SIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.
- MeSH
- adipogeneze * genetika MeSH
- buňky 3T3-L1 * MeSH
- epigeneze genetická * genetika MeSH
- histony metabolismus genetika MeSH
- lidé MeSH
- mutace MeSH
- myši MeSH
- obezita genetika metabolismus MeSH
- posttranslační úpravy proteinů genetika MeSH
- sirtuiny * genetika metabolismus MeSH
- tukové buňky * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Vedecká obec postupne rozuzluje etiologické faktory a patogenetické mechanizmy neurodegeneratívnych ochorení. Z roka na rok pribúdajú dôkazy o čoraz väčšej sile genetického pozadia ako etiologického faktora. V našom príspevku integrujeme dve roviny pohľadu na genetiku Alzheimerovej choroby a príbuzných demencií. V prvej časti článku sumarizujeme súčasné poznatky o genetickom pozadí neurodegeneratívnych demencií s hlavným zameraním sa na Alzheimerovu chorobu. Okrem "klasických" kauzálnych génov a génov susceptibility prinášame prehľad vybraných "nových" génov, ktorých polymorfizmy môžu zvyšovať náchylnosť na Alzheimerovu chorobu. V druhej časti - Skúsenosti z jedného centra - prinášame pohľad na vývoj a súčasný koncept genetického testovania na I. neurologickej klinike v Bratislave. Predstavujeme panel génov pre demencie, ktorý v súčasnosti zahŕňa 45 génov zapojených do patogenézy Alzheimerovej choroby, frontotemporálnej demencie, Parkinsonovej choroby a zriedkavých demencií. V blízkej budúcnosti ho plánujeme rozšíriť na 150-génový panel a postupne kontinuálne aktualizovať. Rozsah genetického testovania, ktorý prinášame v tomto príspevku, sa vzťahuje hlavne na kliniky špecializované na demencie a špecializované centrá pre demencie. Načrtávame koncept, akým by sa mohlo testovanie uberať do budúcnosti na príklade konceptu testovania na našej I. neurologickej klinike. V každom prípade sa snažíme priblížiť problematiku aj ostatným neurologickým klinikám, oddeleniam a ambulanciám, ktoré sa rovnako môžu zapojiť do tohto systému, ak majú vhodných pacientov. Článok ukončujeme kapitolou o relativite súčasných poznatkov, ktorá odzrkadľuje turbulentnú tému genetiky Alzheimerovej choroby, ktorá sa neustále mení, rozširuje, aktualizuje a možno prinesie odpovede na množstvo v súčasnosti nezodpovedaných otázok.
The scientific community is gradually unraveling the etiological factors and pathogenetic mechanisms of neurodegenerative diseases. From year to year there is the robust evidence of the increasing power of the genetic background as an etiological factor. In our paper, we integrate two levels of insight into the genetics of Alzheimer's disease and related dementias. In the first part of the article, we summarize current knowledge about the genetic background of neurodegenerative dementias, with the main focus on Alzheimer's disease. In addition to "classic" causal genes and susceptibility genes, we provide an overview of selected "new" genes whose polymorphisms can increase susceptibility to Alzheimer's disease. In the second part - Experience from one center - we present an insight into the development and current concept of genetic testing at the I. Neurological Clinic. We present a dementia gene panel that currently includes 45 genes involved in the pathogenesis of Alzheimer's disease, Frontotemporal dementia, Parkinson's disease and rare dementias. In the near future, we plan to expand it to a 150 gene panel and gradually update it continuously. The scope of genetic testing that we present in this manuscript mainly applies to dementia clinics and dementia centers. We outline the concept of how testing should proceed in the future using the example of the testing concept at our I. Neurological Clinic. In any case, we are trying to bring this issue closer to other neurological clinics, departments and outpatient clinics, which can also join this system if they have suitable patients. We conclude the article with a chapter on the relativity of current knowledge, which reflects the turbulent topic of the genetics of Alzheimer's disease, which is constantly changing, expanding and updating, and may bring answers to a number of currently unanswered questions.
- MeSH
- Alzheimerova nemoc * diagnóza genetika klasifikace MeSH
- amyloidový prekurzorový protein beta analýza genetika MeSH
- apolipoproteiny E analýza genetika klasifikace MeSH
- epigeneze genetická genetika MeSH
- genetické pozadí MeSH
- genetické testování * metody MeSH
- lidé MeSH
- preseniliny analýza genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Geografické názvy
- Slovenská republika MeSH
- MeSH
- apolipoproteiny E genetika škodlivé účinky MeSH
- epigeneze genetická fyziologie genetika MeSH
- geny * fyziologie genetika MeSH
- komplement - faktor H genetika škodlivé účinky MeSH
- lidé MeSH
- makulární degenerace * genetika patofyziologie MeSH
- retinální drúzy patologie MeSH
- riziko MeSH
- životní styl MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Správné řízení genové exprese hraje zásadní roli v diferenciaci hematopoetických kmenových buněk a dalších procesech hematopoézy. Zásah do epigenetické regulace genové exprese charakterizuje patogenezi celé řady nejen hematologických malignit. V genomech pacientů s akutní myeloidní leukemií, zejména ve skupině s normálním karyotypem, byly opakovaně prokázány somatické mutace v epigenetických regulátorech vč. DNMT3A, TET2, IDH1, IDH2, ASXL1, MLL nebo EZH2. Jedná se o časné preleukemické zásahy, které bývají stabilním ukazatelem klinického vývoje onemocnění a v kombinaci s „driver“ mutacemi (NPM1, FLT3, MLL, RUNX1 aj.) představují kandidátní markery pro monitorování minimální reziduální nemoci. Specifický mutační profil každého pacienta získaný s využitím moderních molekulárních metod, jako je sekvenování nové generace, může přinést zásadní informaci o případném rozvoji relapsu či dosažení remise onemocnění. Cílem této práce je shrnout poznatky o klinickém, biologickém a terapeutickém významu mutací vybraných epigenetických regulátorů rekurentních u akutní myeloidní leukemie.
Regulation of gene expression, especially in hematopoietic stem cells, plays an essential role in differentiation and other important processes of haematopoiesis. Pathogenesis of different malignant diseases is characterised by disruption of epigenetic regulation. Certain somatic mutations, including genes such as DNMT3A, TET2, IDH1, IDH2, ASXL1, MLL or EZH2, have been found in acute myeloid leukaemia, especially in patients with normal karyotype AML. These mutations are considered to be pre-leukemic events and are stable indicators of clinical course. In combination with driver mutations, they are suitable markers for monitoring minimal residual disease. Specific mutational profiles of individual patients could provide essential information about disease progression, relapse or achievement of complete remission. The aim of this article is to review current knowledge regarding the clinical and therapeutical value of mutations in selected genes involved in epigenetic regulation of gene expression in acute myeloid leukaemia.
- MeSH
- akutní myeloidní leukemie * diagnóza farmakoterapie genetika MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- cílená molekulární terapie MeSH
- epigeneze genetická * genetika MeSH
- lidé MeSH
- metylace DNA MeSH
- mutace genetika MeSH
- prognóza MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. METHODS: The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. RESULTS: TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. CONCLUSIONS: Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.
- MeSH
- epigeneze genetická genetika MeSH
- hepatocelulární karcinom farmakoterapie MeSH
- lidé MeSH
- morfoliny farmakologie terapeutické užití MeSH
- myši inbrední NOD MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory jater farmakoterapie MeSH
- proliferace buněk MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie terapeutické užití MeSH
- sorafenib farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Methylation systems have been conserved during the divergence of plants and animals, although they are regulated by different pathways and enzymes. However, studies on the interactions of the epigenomes among evolutionarily distant organisms are lacking. To address this, we studied the epigenetic modification and gene expression of plant chromosome fragments (~30 Mb) in a human-Arabidopsis hybrid cell line. The whole-genome bisulfite sequencing results demonstrated that recombinant Arabidopsis DNA could retain its plant CG methylation levels even without functional plant methyltransferases, indicating that plant DNA methylation states can be maintained even in a different genomic background. The differential methylation analysis showed that the Arabidopsis DNA was undermethylated in the centromeric region and repetitive elements. Several Arabidopsis genes were still expressed, whereas the expression patterns were not related to the gene function. We concluded that the plant DNA did not maintain the original plant epigenomic landscapes and was under the control of the human genome. This study showed how two diverging genomes can coexist and provided insights into epigenetic modifications and their impact on the regulation of gene expressions between plant and animal genomes.
- MeSH
- Arabidopsis genetika MeSH
- buněčné linie MeSH
- chromozomy rostlin genetika MeSH
- DNA rostlinná genetika MeSH
- epigeneze genetická genetika MeSH
- epigenom genetika MeSH
- epigenomika metody MeSH
- genom rostlinný genetika MeSH
- hybridní buňky fyziologie MeSH
- lidé MeSH
- methyltransferasy genetika MeSH
- metylace DNA genetika MeSH
- repetitivní sekvence nukleových kyselin genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
DNA methylation, i.e., addition of methyl group to 5'-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene expression, and thus implied in many cellular processes. Deregulation of DNA methylation is strongly associated with onset of various diseases, including cancer. Here, we review how DNA methylation affects carcinogenesis process and give examples of solid tumors where aberrant DNA methylation is often present. We explain principles of methods developed for DNA methylation analysis at both single gene and whole genome level, based on (i) sodium bisulfite conversion, (ii) methylation-sensitive restriction enzymes, and (iii) interactions of 5-methylcytosine (5mC) with methyl-binding proteins or antibodies against 5mC. In addition to standard methods, we describe recent advances in next generation sequencing technologies applied to DNA methylation analysis, as well as in development of biosensors that represent their cheaper and faster alternatives. Most importantly, we highlight not only advantages, but also disadvantages and challenges of each method.
- MeSH
- 5-methylcytosin metabolismus MeSH
- biosenzitivní techniky metody MeSH
- epigeneze genetická genetika MeSH
- lidé MeSH
- metylace DNA genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
PURPOSE OF REVIEW: Testicular germ cell tumours (TGCTs) exhibit, in contrast to other cancer types, a relatively low mutational burden. However, numerous epigenetic alterations have been shown to impact TGCT. In this review, we summarize the most relevant findings of the past 2 years. RECENT FINDINGS: Recent studies focused on the functions of microRNAs and the impact of aberrant DNA methylation. Moreover, several epigenetic drugs with antineoplastic effects in TGCTs were identified. SUMMARY: Aberrant DNA methylation and differentially expressed microRNAs have an important effect on TGCT pathogenesis. Moreover, differential DNA methylation patterns were found to be specific for different TGCT subtypes. Various microRNAs, such as miR-371a-3p, were found to be highly sensitive and specific biomarkers for TGCT. The epigenetic drugs guadecitabine, animacroxam, and JQ1 showed promising effects on TGCT in preclinical in-vivo and in-vitro studies.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- azacytidin analogy a deriváty terapeutické užití MeSH
- azepiny terapeutické užití MeSH
- cinnamáty terapeutické užití MeSH
- epigeneze genetická genetika MeSH
- germinální a embryonální nádory farmakoterapie genetika MeSH
- imidazoly terapeutické užití MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- mikro RNA genetika MeSH
- nádorové biomarkery genetika MeSH
- nekódující RNA genetika MeSH
- testikulární nádory farmakoterapie genetika MeSH
- triazoly terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
