Chronically undernourished children become stunted during their first 2 years and thereafter bear burdens of ill health for the rest of their lives. Contributors to stunting include poor nutrition and exposure to pathogens, and parental history may also play a role. However, the epigenetic impact of a poor environment on young children is largely unknown. Here we show the unfolding pattern of histone H3 lysine 4 trimethylation (H3K4me3) in children and mothers living in an urban slum in Dhaka, Bangladesh. A pattern of chromatin modification in blood cells of stunted children emerges over time and involves a global decrease in methylation at canonical locations near gene start sites and increased methylation at ectopic sites throughout the genome. This redistribution occurs at metabolic and immune genes and was specific for H3K4me3, as it was not observed for histone H3 lysine 27 acetylation in the same samples. Methylation changes in stunting globally resemble changes that occur in vitro in response to altered methylation capacity, suggesting that reduced levels of one-carbon nutrients in the diet play a key role in stunting in this population. A network of differentially expressed genes in stunted children reveals effects on chromatin modification machinery, including turnover of H3K4me3, as well as posttranscriptional gene regulation affecting immune response pathways and lipid metabolism. Consistent with these changes, reduced expression of the endocytic receptor gene LDL receptor 1 (LRP1) is a driver of stunting in a mouse model, suggesting a target for intervention.

• MeSH
• epigeneze genetická MeSH
• histony genetika   MeSH
• kojenec MeSH
• lidé MeSH
• metylace MeSH
• myši MeSH
• novorozenec MeSH
• podvýživa genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

To study 3D nuclear distributions of epigenetic histone modifications such as H3(K9) acetylation, H3(K4) dimethylation, H3(K9) dimethylation, and H3(K27) trimethylation, and of histone methyltransferase Suv39H1, we used advanced image analysis methods, combined with Nipkow disk confocal microscopy. Total fluorescence intensity and distributions of fluorescently labelled proteins were analyzed in formaldehyde-fixed interphase nuclei. Our data showed reduced fluorescent signals of H3(K9) acetylation and H3(K4) dimethylation (di-me) at the nuclear periphery, while dimeH3( K9) was also abundant in chromatin regions closely associated with the nuclear envelope. Little overlapping (intermingling) was observed for di-meH3(K4) and H3(K27) trimethylation (tri-me), and for di-meH3(K9) and Suv39H1. The histone modifications studied were absent in the nucleolar compartment with the exception of H3(K9) dimethylation that was closely associated with perinucleolar regions which are formed by centromeres of acrocentric chromosomes. Using immunocytochemistry, no di-meH3(K4) but only dense di-meH3(K9) was found for the human acrocentric chromosomes 14 and 22. The active X chromosome was observed to be partially acetylated, while the inactive X was more condensed, located in a very peripheral part of the interphase nuclei, and lacked H3(K9) acetylation. Our results confirmed specific interphase patterns of histone modifications within the interphase nuclei as well as within their chromosome territories.

• MeSH
• acetylace účinky léků   MeSH
• centromera genetika   metabolismus   MeSH
• chromozom X genetika   metabolismus   MeSH
• financování organizované využití   MeSH
• histony metabolismus   MeSH
• interfáze fyziologie   genetika   MeSH
• interpretace obrazu počítačem metody   využití   MeSH
• konfokální mikroskopie metody   využití   MeSH
• metylace účinky léků   MeSH

Epigenetic modifications, such as acetylation, phosphorylation, methylation, ubiquitination, and ADP ribosylation, of the highly conserved core histones, H2A, H2B, H3, and H4, influence the genetic potential of DNA. The enormous regulatory potential of histone modification is illustrated in the vast array of epigenetic markers found throughout the genome. More than the other types of histone modification, acetylation and methylation of specific lysine residues on N-terminal histone tails are fundamental for the formation of chromatin domains, such as euchromatin, and facultative and constitutive heterochromatin. In addition, the modification of histones can cause a region of chromatin to undergo nuclear compartmentalization and, as such, specific epigenetic markers are non-randomly distributed within interphase nuclei. In this review, we summarize the principles behind epigenetic compartmentalization and the functional consequences of chromatin arrangement within interphase nuclei.

• MeSH
• acetylace MeSH
• buněčné jádro metabolismus   ultrastruktura   MeSH
• chromatin ultrastruktura   MeSH
• chromozomální proteiny, nehistonové fyziologie   MeSH
• epigeneze genetická MeSH
• exprese genu MeSH
• financování organizované MeSH
• histony genetika   metabolismus   MeSH
• interfáze MeSH
• lidé MeSH
• lidské chromozomy X metabolismus   MeSH
• metylace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

Molecular changes associated with malignancy are extremely complex. Early epigenetic events occurring in the common tumor types such as breast or prostate cancer might determine the subsequent genetic changes leading to tumor development and progression. Covalent modifications of histones play a major role as determiners of epigenetic information and are important in the regulation of gene expression. Acetylation generally correlates with transcriptional activation, while methylation can signal either activation or repression. However, little is known about the interplay of different epigenetic events. Steroid hormones regulate many cellular processes through signal transduction pathways that result in a variety of post-translational modifications. Such modifications can be triggered by steroid hormones in cooperation with coactivators(p160 family proteins, CBP, p300, p/CAF) and/or corepressors (N-Cor, SMRT, TZF). There is still much to learn about their regulation and the molecular and physiological consequences of these modifications.

• MeSH
• acetylace MeSH
• financování organizované MeSH
• histony metabolismus   MeSH
• lidé MeSH
• metylace MeSH
• pohlavní steroidní hormony metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• steroidní receptory fyziologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Understanding the epigenetics of tumor cells is of clinical significance for the treatment of cancer, and thus, chemists have focused their efforts on the synthesis of new generation of inhibitors of histone deacetylases (HDACs) or methylation-specific enzymes as novel important anti-cancer drugs. Here, we tested whether the histone signature and DNA methylation in multiple myeloma (MM) and leukemia cells is tumor-specific as compared with that in non-malignant lymphoblastoid cells. We observed a distinct histone signature in c-myc, Mcl-1, and ribosomal gene loci in MOLP8 MM and K562 leukemia cells, when compared with lymphoblastoid cells. Histone and DNA methylation patterns in MOLP8 cells were partially modified by the clinically promising HDAC inhibitor, vorinostat. In comparison with lymphoblastoid WIL2NS cells, MOLP8 cells and K562 cells were characterized by an absence of the gene silencing marker H3K9me2 in the c-myc and ribosomal genes. However, high levels of H3K27me3 were detected in the promoters and coding regions of selected genomic regions in these cells. Treatment by vorinostat increased the level of DNA methylation at the c-myc promoter, and this alteration was accompanied by a decrease in c-MYC protein. In MOLP8 cells, vorinostat significantly increased the H3K9 acetylation in the Mcl-1 coding regions and promoter. Both MOLP8 and K562 leukemia cells were characterized by decreased levels of H3K9me2 in the Mcl-1 gene as compared with lymphoblastoid WIL2NS cells. Lower levels of H3K9me1 in the Mcl-1 promoter, however, were specific for MM cells as compared with the other cell types studied. In other MM and leukemia cell lines, COLO677, OPM2, and U937, the ribosomal genes were less prone to epigenetic heterogeneity as compared to the c-myc and Mcl-1 proto-oncogenes. Taken together, these data describe both tumor-specific and loci-specific histone signature and DNA methylation profiles.

• MeSH
• chromatinová imunoprecipitace MeSH
• epigeneze genetická genetika   MeSH
• fluorescenční protilátková technika MeSH
• histony genetika   MeSH
• leukemie genetika   MeSH
• lidé MeSH
• metylace DNA MeSH
• mnohočetný myelom genetika   MeSH
• nádorové buněčné linie MeSH
• promotorové oblasti (genetika) genetika   MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• azacytidin analogy a deriváty   terapeutické užití   MeSH
• DNA-(cytosin-5-)methyltransferasa antagonisté a inhibitory   chemie   MeSH
• epigeneze genetická MeSH
• heterochromatin chemie   MeSH
• histonový kód MeSH
• klinické zkoušky jako téma MeSH
• metylace DNA MeSH
• myelodysplastické syndromy farmakoterapie   genetika   MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biologie
• hematologie a transfuzní lékařství
• onkologie

• MeSH
• chronická fáze myeloidní leukemie genetika   MeSH
• histony MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové buňky kultivované MeSH
• retinoblastom MeSH
• RNA MeSH
• sekvence nukleotidů MeSH
• Check Tag
• lidé MeSH

Metylace DNA je vedle acetylace histonových proteinů jedním ze dvou globálních mechanizmů, kterým je řízena genová exprese. Profily metylace DNA se během vývoje organizmu i v průběhu nádorového onemocnění mění. V nádorových buňkách jsou pozorovány tři změny profilů metylace DNA: hypometylace, hypermetylace a ztráta imprintingu. Metylaci DNA lze považovat vedle intragenové mutace a ztráty heterozygozity za třetí cestu inaktivace tumor-supresorových genů v genezi nádorového onemocnění. V předkládaném přehledném článku popisujeme nedávné poznatky a hypotézy o úloze metylace DNA při vzniku nádorového onemocnění a uvádíme možné aplikace v diagnostice a terapii nádorových onemocnění.

DNA methylation and acetylation of histone proteins represent two global mechanisms controlling the gene expression. DNA methylation profiles alter during the development of the organism and during progression of neoplasia. Three types of alterations of the DNA methylation profiles were observed in the tumor cells: hypo- methylation, hypermethylation and the loss of imprinting. Beside the intra-gene mutation and the heterozygosity absence, DNA methylation can be understood as the third mechanism of tumor-suppressor gene inactivation in the genesis of neoplasia. Our review article brings recent findings and hypotheses on the role of DNA methylation in the carcinogenesis and its possible application in the diagnostics and therapy of the malignant proliferation.

• MeSH
• DNA modifikační methylasy MeSH
• mutageneze MeSH
• nádory diagnóza   genetika   MeSH
• regulace genové exprese MeSH

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve >0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.

• MeSH
• dítě MeSH
• histony genetika   MeSH
• lidé MeSH
• lipasa genetika   MeSH
• membránové proteiny genetika   MeSH
• metylace DNA genetika   MeSH
• mladiství MeSH
• nealkoholová steatóza jater * diagnóza   MeSH
• pilotní projekty MeSH
• volné cirkulující nukleové kyseliny * metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH

Methylation of histone H3 at lysine 36 (H3K36me3) marks active chromatin. The mark is interpreted by epigenetic readers that assist transcription and safeguard the integrity of the chromatin fiber. The chromodomain protein MSL3 binds H3K36me3 to target X-chromosomal genes in male Drosophila for dosage compensation. The PWWP-domain protein JASPer recruits the JIL1 kinase to active chromatin on all chromosomes. Unexpectedly, depletion of K36me3 had variable, locus-specific effects on the interactions of those readers. This observation motivated a systematic and comprehensive study of K36 methylation in a defined cellular model. Contrasting prevailing models, we found that K36me1, K36me2 and K36me3 each contribute to distinct chromatin states. A gene-centric view of the changing K36 methylation landscape upon depletion of the three methyltransferases Set2, NSD and Ash1 revealed local, context-specific methylation signatures. Set2 catalyzes K36me3 predominantly at transcriptionally active euchromatin. NSD places K36me2/3 at defined loci within pericentric heterochromatin and on weakly transcribed euchromatic genes. Ash1 deposits K36me1 at regions with enhancer signatures. The genome-wide mapping of MSL3 and JASPer suggested that they bind K36me2 in addition to K36me3, which was confirmed by direct affinity measurement. This dual specificity attracts the readers to a broader range of chromosomal locations and increases the robustness of their actions.

• MeSH
• chromatin * metabolismus   MeSH
• DNA vazebné proteiny metabolismus   genetika   MeSH
• Drosophila melanogaster genetika   metabolismus   MeSH
• heterochromatin metabolismus   genetika   MeSH
• histonlysin-N-methyltransferasa * metabolismus   genetika   MeSH
• histony * metabolismus   MeSH
• lysin metabolismus   MeSH
• methyltransferasy metabolismus   genetika   MeSH
• metylace MeSH
• protein-serin-threoninkinasy MeSH
• proteiny Drosophily * metabolismus   genetika   MeSH
• transkripční faktory metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH