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1.
Adv Exp Med Biol ; 1396: 3-16, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36454456

RESUMO

This chapter summarizes the definition, classification, and function of genome editing and highlights the breakthroughs of genome editing in cardiovascular and metabolic diseases for disease modeling, diagnostics, and therapeutics, with a particular focus on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated 9 (Cas9) technology as applied to nuclease editing, base editing, and epigenome editing.


Assuntos
Sistema Cardiovascular , Doenças Metabólicas , Humanos , Edição de Genes , Doenças Metabólicas/genética , Doenças Metabólicas/terapia , Endonucleases , Epigenoma
2.
Methods Mol Biol ; 2577: 255-268, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36173579

RESUMO

Epigenetic regulatory mechanisms play an important role in gene silencing and genome stability; therefore, epigenetic mutations cause a variety of diseases. Analysis of the epigenome by next-generation sequencers has revealed many epigenetic mutations in various diseases such as cancer, obesity, diabetes, autism, allergies, immune diseases, and imprinting diseases. Unfortunately, it has been difficult to identify the causative epigenetic mutations because there has been no method to generate animals with target-specific epigenetic mutations. However, it has become possible to generate such animals due to the recent development of epigenome editing technology. Here, we introduce the generation of epigenome-edited mice by target-specific DNA demethylation.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Animais , Desmetilação do DNA , Metilação de DNA , Epigênese Genética , Epigenoma , Edição de Genes/métodos , Camundongos
3.
J Hazard Mater ; 441: 129843, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36113351

RESUMO

Cadmium (Cd) is the most widely distributed heavy metal pollutant in soil and has significant negative effects on crop yields and human health. Rhizobia can enhance soybean growth in the presence of heavy metals, and the legume-rhizobia symbiosis has been used to promote heavy-metal phytoremediation, but much remains to be learned about the molecular networks that underlie these effects. Here, we demonstrated that soybean root growth was strongly suppressed after seven days of Cd exposure but that the presence of rhizobia largely eliminated this effect, even prior to nodule development. Moreover, rhizobia did not appear to promote root growth by limiting plant Cd uptake: seedlings with and without rhizobia had similar root Cd concentrations. Previous studies have demonstrated a role for m6A RNA methylation in the response of rice and barley to Cd stress. We therefore performed transcriptome-wide m6A methylation profiling to investigate changes in the soybean RNA methylome in response to Cd with and without rhizobia. Here, we provide some of the first data on transcriptome-wide m6a RNA methylation patterns in soybean; m6A modifications were concentrated at the 3' UTR of transcripts and showed a positive relationship with transcript abundance. Transcriptome-wide m6A RNA methylation peaks increased in the presence of Cd, and the integration of m6A methylome and transcriptome results enabled us to identify 154 genes whose transcripts were both differentially methylated and differentially expressed in response to Cd stress. Annotation results suggested that these genes were associated with Ca2+ homeostasis, ROS pathways, polyamine metabolism, MAPK signaling, hormones, and biotic stress responses. There were 176 differentially methylated and expressed transcripts under Cd stress in the presence of rhizobia. In contrast to the Cd-only gene set, they were also enriched in genes related to auxin, jasmonic acid, and brassinosteroids, as well as abiotic stress tolerance. They contained fewer genes related to Ca2+ homeostasis and also included candidates with known functions in the legume-rhizobia symbiosis. These findings offer new insights into how rhizobia promote soybean root growth under Cd stress; they provide candidate genes for research on plant heavy metal responses and for the use of legumes in phytoremediation.


Assuntos
Poluentes Ambientais , Fabaceae , Metais Pesados , Rhizobium , Regiões 3' não Traduzidas , Brassinosteroides , Cádmio/metabolismo , Cádmio/toxicidade , Poluentes Ambientais/metabolismo , Epigenoma , Fabaceae/metabolismo , Hormônios/metabolismo , Humanos , Ácidos Indolacéticos , Metais Pesados/metabolismo , Metais Pesados/toxicidade , Poliaminas/metabolismo , RNA de Plantas/genética , Espécies Reativas de Oxigênio/metabolismo , Rhizobium/metabolismo , Solo , Soja/genética , Soja/metabolismo
4.
Methods Mol Biol ; 2588: 295-315, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418695

RESUMO

-Omics analyses, including the systematic cataloging of messenger RNA and microRNA sequences or DNA methylation patterns in a cell population, organ, or tissue sample, are powerful means of generating comprehensive genome-level data sets on complex diseases. We have systematically assessed the transcriptome, microbiome, miRNome, and methylome of gingival and peri-implant tissues from human subjects and further studied the transcriptome of primary cells ex vivo, or in vitro after infection with periodontal pathogens.Our data offer new insight on the pathophysiology underlying periodontal and peri-implant diseases, a possible route to a better and earlier diagnosis of these highly prevalent chronic inflammatory diseases and thus, to a personalized and efficient treatment approach.Herein, we outline the laboratory steps required for the processing of periodontal cells and tissues for -omics analyses using current microarrays or next-generation sequencing technology.


Assuntos
MicroRNAs , Próteses e Implantes , Humanos , Epigenoma , MicroRNAs/genética , Sequenciamento de Nucleotídeos em Larga Escala , Transcriptoma
5.
Clin Epigenetics ; 14(1): 159, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36457109

RESUMO

BACKGROUND: The epigenetic regulation of the renin-angiotensin-aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). Here we report the first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations and the aldosterone-to-renin ratio (ARR). METHODS: Epigenome-wide DNA methylation was measured using the Illumina 450K array on whole blood samples of 68 Ghanaians. Differentially methylated positions (DMPs) were assessed for plasma renin concentration, aldosterone, and ARR using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, hypertension, and technical covariates. Additionally, we extracted methylation loci previously associated with hypertension, kidney function, or that were annotated to RAAS-related genes and associated these with renin and aldosterone concentration. RESULTS: We identified one DMP for renin, ten DMPs for aldosterone, and one DMP associated with ARR. Top DMPs were annotated to the PTPRN2, SKIL, and KCNT1 genes, which have been reported in relation to cardiometabolic risk factors, atherosclerosis, and sodium-potassium handling. Moreover, EWAS loci previously associated with hypertension, kidney function, or RAAS-related genes were also associated with renin, aldosterone, and ARR. CONCLUSION: In this first EWAS on RAAS hormones, we identified DMPs associated with renin, aldosterone, and ARR in a SSA population. These findings are a first step in understanding the role of DNA methylation in regulation of the RAAS in general and in a SSA population specifically. Replication and translational studies are needed to establish the role of these DMPs in the hypertension burden in SSA populations.


Assuntos
Hipertensão , Renina , Humanos , Renina/genética , Aldosterona , Gana , Epigenoma , Epigênese Genética , Metilação de DNA , Hipertensão/genética , Canais de Potássio Ativados por Sódio , Proteínas do Tecido Nervoso
6.
Clin Epigenetics ; 14(1): 158, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36457128

RESUMO

BACKGROUND: Epigenome-wide association studies (EWAS) have helped to define the associations between DNA methylation and many clinicopathologic and developmental traits. Since DNA methylation is affected by genetic variation at certain loci, EWAS associations may be potentially influenced by genetic effects. However, a formal assessment of the value of incorporating genetic variation in EWAS evaluations is lacking especially for multiethnic populations. METHODS: Using single nucleotide polymorphism (SNP) from Illumina Omni Express or Affymetrix PMDA arrays and DNA methylation data from the Illumina 450 K or EPIC array from 1638 newborns of diverse genetic ancestries, we generated DNA methylation quantitative trait loci (mQTL) databases for both array types. We then investigated associations between neonatal DNA methylation and birthweight (incorporating gestational age) using EWAS modeling, and reported how EWAS results were influenced by controlling for mQTLs. RESULTS: For CpGs on the 450 K array, an average of 15.4% CpGs were assigned as mQTLs, while on the EPIC array, 23.0% CpGs were matched to mQTLs (adjusted P value < 0.05). The CpGs associated with SNPs were enriched in the CpG island shore regions. Correcting for mQTLs in the EWAS model for birthweight helped to increase significance levels for top hits. For CpGs overlapping genes associated with birthweight-related pathways (nutrition metabolism, biosynthesis, for example), accounting for mQTLs changed their regression coefficients more dramatically (> 20%) than for other random CpGs. CONCLUSION: DNA methylation levels at circa 20% CpGs in the genome were affected by common SNP genotypes. EWAS model fit significantly improved when taking these genetic effects into consideration. Genetic effects were stronger on CpGs overlapping genetic elements associated with control of gene expression.


Assuntos
Epigenoma , Locos de Características Quantitativas , Recém-Nascido , Humanos , Metilação de DNA , Peso ao Nascer/genética , Ilhas de CpG
7.
FEBS Open Bio ; 12(12): 2227-2235, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36342317

RESUMO

Rheumatoid arthritis (RA) is highly heritable, and previous studies have suggested that genetic variation may affect susceptibility to RA by altering epigenetic modifications (e.g. DNA methylation). Here we examined how genetic variation influences DNA methylation (DNAm) in RA by integrating individual genetic variation and DNAm data. Epigenome-wide meQTL (methylation quantitative trait loci) analysis was performed on 354 RA patients and 335 controls, scanning 30,101,744 relationships between 62 SNPs and 485,512 DNA methylation sites. Two regulatory relationship pairs (FDR < 0.05) showed very strong associations with RA risk. One was rs10796216-cg00475509, and the DNAm decreased by 0.0168 per addition of allele rs10796216-A. The other was rs6546473-cg13358873, for which a 0.0365 reduction of DNAm at cg13358873 was observed for each addition of allele rs6546473-A, and lower DNAm was found to be significantly associated with RA risk (P = 2.0407e-28). Moreover, both pairs of meQTL showed a strong regulatory relationship only in RA samples, so they can be subsequently considered as risk markers for RA. In conclusion, our integrated analysis of genetic and epigenetic variation suggests that genetic variation may affect the risk of RA by regulating DNA methylation levels. Alterations of DNAm at cg00475509 and cg13358873 loci conferred by rs10796216-A and rs6546473-A allele may suggest a potential risk for RA. Our results deepen our understanding of the genetic and epigenetic mechanisms of RA and provide novel associations that can be further investigated in future studies.


Assuntos
Artrite Reumatoide , Epigenoma , Locos de Características Quantitativas , Humanos , Artrite Reumatoide/genética , Metilação de DNA , Epigênese Genética
8.
Biochem Biophys Res Commun ; 637: 50-57, 2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36375250

RESUMO

Aberrant DNA methylation is associated with oncogenesis of various human cancers, including pancreatic cancer (PC). PC is the seventh most common cancer, and obesity is a known high-risk factor. However, whether obesity influences DNA methylation in pancreatic exocrine cells and if this influences PC development remain unclear. Here, we performed an epigenome-wide analysis of isolated pancreatic exocrine cells obtained from mice with high-fat-diet-induced obesity (DIO). Using the Illumina Mouse Methylation BeadChip array (280K), we identified 316 differentially methylated regions (DMRs) that were enriched for cellular processes, such as DNA repair, transcription regulation, and cell proliferation, which confirmed obesity-related dysregulation of certain metabolic processes in the pancreatic cells in DIO mice. Comparing the DMRs with those in stage IB PC helped identify 82 overlapping DMRs. Three pathways including the cell hypertrophy pathway involving PLC, PKC, SMAD2/3, and TRKA; the metabolic control pathway involving CREB and AMPK; and the potassium regulation pathway involving K+-channels, were shared between the pancreatic exocrine cells from DIO mice and stage IB PC. Enhanced alteration in the methylation level was observed in PC compared to that in DIO mice. These findings indicated that obesity influences DNA methylation in pancreatic exocrine cells of DIO mice, and persistent dysregulation of DNA methylation in individuals with obesity may result in PC development.


Assuntos
Epigenoma , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Metilação de DNA , Dieta Hiperlipídica/efeitos adversos , Obesidade/complicações , Obesidade/genética , Camundongos Obesos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/complicações , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Epigênese Genética
9.
Sci Rep ; 12(1): 20166, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36424439

RESUMO

An epigenome-wide association study (EWAS) was performed on buccal cells from monozygotic-twins (MZ) reared together as children, but who live apart as adults. Cohorts of twin pairs were used to investigate associations between neighborhood walkability and objectively measured physical activity (PA) levels. Due to dramatic cellular epigenetic sex differences, male and female MZ twin pairs were analyzed separately to identify differential DNA methylation regions (DMRs). A priori comparisons were made on MZ twin pairs discordant on body mass index (BMI), PA levels, and neighborhood walkability. In addition to direct comparative analysis to identify specific DMRs, a weighted genome coexpression network analysis (WGCNA) was performed to identify DNA methylation sites associated with the physiological traits of interest. The pairs discordant in PA levels had epigenetic alterations that correlated with reduced metabolic parameters (i.e., BMI and waist circumference). The DNA methylation sites are associated with over fifty genes previously found to be specific to vigorous PA, metabolic risk factors, and sex. Combined observations demonstrate that behavioral factors, such as physical activity, appear to promote systemic epigenetic alterations that impact metabolic risk factors. The epigenetic DNA methylation sites and associated genes identified provide insight into PA impacts on metabolic parameters and the etiology of obesity.


Assuntos
Epigenoma , Gêmeos Monozigóticos , Adulto , Criança , Feminino , Masculino , Humanos , Gêmeos Monozigóticos/genética , Metilação de DNA , Mucosa Bucal , Exercício Físico , DNA
10.
Mol Cell Probes ; 66: 101873, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36379302

RESUMO

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Epigenoma , Detecção Precoce de Câncer , DNA de Neoplasias/genética , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Metilação de DNA/genética
11.
Clin Epigenetics ; 14(1): 142, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329530

RESUMO

BACKGROUND: Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches. RESULTS: Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods-Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine-predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL. CONCLUSIONS: The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.


Assuntos
Neoplasias das Glândulas Suprarrenais , Hipertensão , Feocromocitoma , Humanos , Epigenoma , Metilação de DNA , Feocromocitoma/complicações , Feocromocitoma/genética , Hipertensão/diagnóstico , Hipertensão/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/complicações , Biomarcadores
12.
Nat Commun ; 13(1): 6524, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316347

RESUMO

DNMT3A and IDH1/2 mutations combinatorically regulate the transcriptome and the epigenome in acute myeloid leukemia; yet the mechanisms of this interplay are unknown. Using a systems approach within topologically associating domains, we find that genes with significant expression-methylation correlations are enriched in signaling and metabolic pathways. The common denominator across these methylation-regulated genes is the density in MIR retrotransposons of their introns. Moreover, a discrete number of CpGs overlapping enhancers are responsible for regulating most of these genes. Established mouse models recapitulate the dependency of MIR-rich genes on the balanced expression of epigenetic modifiers, while projection of leukemic profiles onto normal hematopoiesis ones further consolidates the dependencies of methylation-regulated genes on MIRs. Collectively, MIR elements on genes and enhancers are susceptible to changes in DNA methylation activity and explain the cooperativity of proteins in this pathway in normal and malignant hematopoiesis.


Assuntos
Epigenoma , Leucemia Mieloide Aguda , Camundongos , Animais , Retroelementos/genética , Transcriptoma/genética , Mutação , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Metilação de DNA/genética
13.
AAPS J ; 24(6): 115, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36324037

RESUMO

Overexposure to ultraviolet radiation and environmental carcinogens drive skin cancer development through redox imbalance and gene mutation. Antioxidants such as triterpenoids have exhibited anti-oxidative and anti-inflammatory potentials to alleviate skin carcinogenesis. This study investigated the methylome and transcriptome altered by tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or TPA with 2-cyano 2,3-dioxoolean-1,9-dien-28-oic acid (CDDO). The results show that CDDO blocks TPA-induced transformation dose dependently. Several differential expressed genes (DEGs) involved in skin cell transformation, while counteracted by CDDO, were revealed by differential expression analysis including Lyl1, Lad1, and Dennd2d. In CpG methylomic profiles, the differentially methylated regions (DMRs) in the promoter region altered by TPA while showing the opposite methylation status in the CDDO treatment group were identified. The correlation between DNA methylation and RNA expression has been established and DMRs showing inverse correlation were further studied as potential therapeutic targets. From the CpG methylome and transcriptome results, CDDO significantly restored gene expression of NAD(P)H:quinone oxidoreductase 1 (Nqo1) inhibited by TPA by decreasing their promoter CpG methylation. Ingenuity Pathways Analysis (IPA) shows that CDDO neutralized the effect of TPA through modulating cell cycles, cell migration, and inflammatory and immune response regulatory pathways. Notably, Tumor Necrosis Factor Receptor 2 (TNFR2) signaling was significantly downregulated by CDDO potentially contributing to prevention of TPA-induced cell transformation. Overall, incorporating the transcriptome, CpG methylome, and signaling pathway network, we reveal potential therapeutic targets and pathways by which CDDO could reverse TPA-induced carcinogenesis. The results could be useful for future human study and targets development for skin cancer.


Assuntos
Neoplasias Cutâneas , Triterpenos , Humanos , Epigenoma , Acetato de Tetradecanoilforbol/toxicidade , Triterpenos/farmacologia , Transcriptoma , Raios Ultravioleta , Transformação Celular Neoplásica , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
14.
Sci Rep ; 12(1): 18361, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36319817

RESUMO

Epigenetic mechanisms have been hypothesized to play a role in the etiology of major depressive disorder (MDD). In this study, we performed a meta-analysis between two case-control MDD cohorts to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in MDD. Using samples from two Cohorts (a total of 298 MDD cases and 63 controls with repeated samples, on average ~ 1.8 samples/subject), we performed an EWAS meta-analysis. Multiple cytosine-phosphate-guanine sites annotated to TNNT3 were associated with MDD reaching study-wide significance, including cg08337959 (p = 2.3 × 10-11). Among DMPs with association p values less than 0.0001, pathways from REACTOME such as Ras activation upon Ca2+ influx through the NMDA receptor (p = 0.0001, p-adjusted = 0.05) and long-term potentiation (p = 0.0002, p-adjusted = 0.05) were enriched in this study. A total of 127 DMRs with Sidak-corrected p value < 0.05 were identified from the meta-analysis, including DMRs annotated to TNNT3 (chr11: 1948933 to 1949130 [6 probes], Sidak corrected P value = 4.32 × 10-41), S100A13 (chr1: 153599479 to 153600972 [22 probes], Sidak corrected P value = 5.32 × 10-18), NRXN1 (chr2: 50201413 to 50201505 [4 probes], Sidak corrected P value = 1.19 × 10-11), IL17RA (chr22: 17564750 to 17565149, Sidak corrected P value = 9.31 × 10-8), and NPFFR2 (chr4: 72897565 to 72898212, Sidak corrected P value = 8.19 × 10-7). Using 2 Cohorts of depression case-control samples, we identified DMPs and DMRs associated with MDD. The molecular pathways implicated by these data include mechanisms involved in neuronal synaptic plasticity, calcium signaling, and inflammation, consistent with reports from previous genetic and protein biomarker studies indicating that these mechanisms are involved in the neurobiology of depression.


Assuntos
Transtorno Depressivo Maior , Epigenoma , Humanos , Transtorno Depressivo Maior/genética , Metilação de DNA , Estudo de Associação Genômica Ampla , Epigênese Genética
15.
Front Endocrinol (Lausanne) ; 13: 1059085, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36419771

RESUMO

Bidirectional crosstalk between the nuclear and mitochondrial genomes is essential for proper cell functioning. Mitochondrial DNA copy number (mtDNA-CN) and heteroplasmy influence mitochondrial function, which can influence the nuclear genome and contribute to health and disease. Evidence shows that mtDNA-CN and heteroplasmic variation are associated with aging, complex disease, and all-cause mortality. Further, the nuclear epigenome may mediate the effects of mtDNA variation on disease. In this way, mitochondria act as an environmental biosensor translating vital information about the state of the cell to the nuclear genome. Cellular communication between mtDNA variation and the nuclear epigenome can be achieved by modification of metabolites and intermediates of the citric acid cycle and oxidative phosphorylation. These essential molecules (e.g. ATP, acetyl-CoA, ɑ-ketoglutarate and S-adenosylmethionine) act as substrates and cofactors for enzymes involved in epigenetic modifications. The role of mitochondria as an environmental biosensor is emerging as a critical modifier of disease states. Uncovering the mechanisms of these dynamics in disease processes is expected to lead to earlier and improved treatment for a variety of diseases. However, the influence of mtDNA-CN and heteroplasmy variation on mitochondrially-derived epigenome-modifying metabolites and intermediates is poorly understood. This perspective will focus on the relationship between mtDNA-CN, heteroplasmy, and epigenome modifying cofactors and substrates, and the influence of their dynamics on the nuclear epigenome in health and disease.


Assuntos
Genoma Mitocondrial , Genoma Mitocondrial/genética , Epigenoma , DNA Mitocondrial/genética , Mitocôndrias/genética , Genômica
16.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430738

RESUMO

There is an increase in the incidence of early onset colorectal carcinoma (EOCRC). To better understand if there is any difference in molecular pathogenesis of EOCRC and late onset colorectal carcinoma (LOCRC), we compared the clinical, histological, transcriptome, and methylome profile of paired CRC and healthy colonic tissue from 67 EOCRC and 98 LOCRC patients. The frequency of stage 3 CRC, lymph node involvement, lymphovascular invasion, and perineural invasion was higher in the EOCRC group. Many of the cancer related pathways were differentially expressed in CRC tissue in both EOCRC and LOCRC patients. However, the magnitude of differential expression for some groups of genes, such as DNA damage repair genes and replication stress genes, were significantly less pronounced in the EOCRC group, suggesting less efficient DNA damage repair to be associated with EOCRC. A more marked methylation of "growth factor receptor" genes in LOCRC correlated with a more pronounced down-regulation of those genes in that group. From a therapeutic point of view, more over-expression of fatty acid synthase (FASN) among the LOCRC patients may suggest a better response of FASN targeted therapy in that group. The age of onset of CRC did not appear to modify the response of cis-platin or certain immune checkpoint inhibitors. We found some differences in the molecular pathogenesis in EOCRC and LOCRC that may have some biological and therapeutic significance.


Assuntos
Neoplasias Colorretais , Epigenoma , Humanos , Transcriptoma , Neoplasias Colorretais/patologia , Incidência
17.
Transl Psychiatry ; 12(1): 465, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344488

RESUMO

Generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD) had high comorbidity and affected more than 44 million people around the world leading to a huge burden on health and economy. Here, we conducted an epigenome-wide DNA methylation study employing 93 patients with GAD, 65 patients with OCD, and 302 health controls, to explore epigenetic alterations associated with the onset and differences of GAD and OCD. We identified multiple differentially methylated positions (DMPs) and regions (DMRs): three DMP genes included RIOK3 (cg21515243, p = 8.00 × 10-10), DNASE2 (cg09379601, p = 1.10 × 10-9), and PSMB4 (cg01334186, p = 3.70 × 10-7) and two DMR genes USP6NL (p = 4.50 × 10-4) and CPLX1 (p = 6.95 × 10-4) were associated with the onset of GAD and OCD; three DMPs genes included LDLRAP1 (cg21400344, p = 4.40 × 10-12), ACIN1 (cg23712970, p = 2.98×10-11), and SCRT1 (cg25472897, p = 5.60 × 10-11) and three DMR genes WDR19 (p = 3.39 × 10-3), SYCP1 (p = 6.41 × 10-3), and FAM172A (p = 5.74 × 10-3) were associated with the differences between GAD and OCD. Investigation of epigenetic age and chronological age revealed a different epigenetic development trajectory of GAD and OCD. Conclusively, our findings which yielded robust models may aid in distinguishing patients from healthy controls (AUC = 0.90-0.99) or classifying patients with GAD and OCD (AUC = 0.89-0.99), and may power the precision medicine for them.


Assuntos
Epigenoma , Transtorno Obsessivo-Compulsivo , Humanos , Metilação de DNA , Transtornos de Ansiedade , Células Sanguíneas , China , Proteínas Nucleares , Complexo de Endopeptidases do Proteassoma , Proteínas
18.
Clin Epigenetics ; 14(1): 148, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376973

RESUMO

BACKGROUND: The molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor αß-positive CD8+ memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples. RESULTS: We identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation. CONCLUSIONS: DNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed.


Assuntos
Leucemia Linfocítica Granular Grande , Humanos , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/metabolismo , Leucemia Linfocítica Granular Grande/patologia , Epigenoma , Metilação de DNA , Fatores de Transcrição/genética , Biomarcadores/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Repressoras/genética
19.
Pharmacol Ther ; 240: 108301, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36283453

RESUMO

Malignant melanoma is the most lethal type of skin cancer with high rates of mortality. Although current treatment options provide a short-clinical benefit, acquired-drug resistance highlights the low 5-year survival rate among patients with advanced stage of the disease. In parallel, the involvement of an aberrant epigenetic landscape, (e.g., alterations in DNA methylation patterns, histone modifications marks and expression of non-coding RNAs), in addition to the genetic background, has been also associated with the onset and progression of melanoma. In this review article, we report on current therapeutic options in melanoma treatment with a focus on distinct epigenetic alterations and how their reversal, by specific drug compounds, can restore a normal phenotype. In particular, we concentrate on how single and/or combinatorial therapeutic approaches have utilized epigenetic drug compounds in being effective against malignant melanoma. Finally, the role of deregulated epigenetic mechanisms in promoting drug resistance to targeted therapies and immune checkpoint inhibitors is presented leading to the development of newly synthesized and/or improved drug compounds capable of targeting the epigenome of malignant melanoma.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Epigenoma , Melanoma/tratamento farmacológico , Melanoma/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Epigênese Genética , Metilação de DNA
20.
Cancer Discov ; 12(12): 2906-2929, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36305747

RESUMO

Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dismal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of the mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration, and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models. SMARCA4 colocalizes with SOX10 at gene regulatory elements to control the expression of genes involved in cell growth and the extracellular matrix (ECM). Moreover, SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M, a mutation occurring in about 60% DMG tumors. Furthermore, the SMARCA4 occupancy at enhancers marked by both SOX10 and H3K27 acetylation is reduced the most upon depleting the H3.3K27M mutation. Taken together, our results support a model in which epigenome reprogramming by H3.3K27M creates a dependence on SMARCA4-mediated chromatin remodeling to drive gene expression and the pathogenesis of H3.3K27M DMG. SIGNIFICANCE: DMG is a deadly pediatric glioma currently without effective treatments. We discovered that the chromatin remodeler SMARCA4 is essential for the proliferation of DMG with H3K27M mutation in vitro and in vivo, identifying a potentially novel therapeutic approach to this disease. See related commentary by Beytagh and Weiss, p. 2730. See related article by Panditharatna et al., p. 2880. This article is highlighted in the In This Issue feature, p. 2711.


Assuntos
Glioma , Histonas , Animais , Humanos , Criança , Histonas/genética , Histonas/metabolismo , Epigenoma , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Cromatina , Mutação , Células-Tronco Neoplásicas/metabolismo , Mamíferos/genética , Mamíferos/metabolismo , DNA Helicases/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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