Publications by authors named "Juan Castillo-Fernandez"

29 Publications

  • Page 1 of 1

Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis.

Am J Respir Crit Care Med 2022 May 10. Epub 2022 May 10.

University of British Columbia, Department of Medicine, Division of Respiratory Medicine, Vancouver, British Columbia, Canada.

Rationale: Methylation integrates factors present at birth and modifiable across life that can influence pulmonary function. Studies are limited in scope and replication.

Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function.

Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (17,503 individuals: 14,761 European; 2,549 African; and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics.

Measurements And Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that EWAS signals capture causal regulatory genomic loci.

Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies providing insights into lung pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202108-1907OCDOI Listing
May 2022

Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice.

Nat Commun 2022 May 5;13(1):2464. Epub 2022 May 5.

Lymphocyte Development & Epigenetic Memory Groups, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.

Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, modified histones and DNA methylation. Similar processes in mammals can also affect phenotype through intergenerational or trans-generational mechanisms. Here we generate a luciferase knock-in reporter mouse for the imprinted Dlk1 locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternal Dlk1 in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneous Dlk1 mis-expression is seen exclusively among animals born to F1-exposed females. Oocytes from these females show altered gene and microRNA expression without changes in DNA methylation, and correct imprinting is restored in subsequent generations. Our results illustrate how diet impacts the foetal epigenome, disturbing canonical and non-canonical imprinting mechanisms to modulate the properties of successive generations of offspring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-022-30022-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072353PMC
May 2022

Leptin Signaling in the Ovary of Diet-Induced Obese Mice Regulates Activation of NOD-Like Receptor Protein 3 Inflammasome.

Front Cell Dev Biol 2021 3;9:738731. Epub 2021 Nov 3.

Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Poland.

Obesity leads to ovarian dysfunction and the establishment of local leptin resistance. The aim of our study was to characterize the levels of NOD-like receptor protein 3 (NLRP3) inflammasome activation in ovaries and liver of mice during obesity progression. Furthermore, we tested the putative role of leptin on NLRP3 regulation in those organs. C57BL/6J female mice were treated with equine chorionic gonadotropin (eCG) or human chorionic gonadotropin (hCG) for estrous cycle synchronization and ovary collection. In diet-induced obesity (DIO) protocol, mice were fed chow diet (CD) or high-fat diet (HFD) for 4 or 16 weeks, whereas in the hyperleptinemic model (LEPT), mice were injected with leptin for 16 days (16 L) or saline (16 C). Finally, the genetic obese leptin-deficient (+/? and -/-) mice were fed CD for 4 week. Either ovaries and liver were collected, as well as cumulus cells (CCs) after superovulation from DIO and LEPT. The estrus cycle synchronization protocol showed increased protein levels of NLRP3 and interleukin (IL)-18 in diestrus, with this stage used for further sample collections. In DIO, protein expression of NLRP3 inflammasome components was increased in 4 week HFD, but decreased in 16 week HFD. Moreover, NLRP3 and IL-1β were upregulated in 16 L and downregulated in Transcriptome analysis of CC showed common genes between LEPT and 4 week HFD modulating NLRP3 inflammasome. Liver analysis showed NLRP3 protein upregulation after 16 week HFD in DIO, but also its downregulation in . We showed the link between leptin signaling and NLRP3 inflammasome activation in the ovary throughout obesity progression in mice, elucidating the molecular mechanisms underpinning ovarian failure in maternal obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.738731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595835PMC
November 2021

Identical twins carry a persistent epigenetic signature of early genome programming.

Nat Commun 2021 09 28;12(1):5618. Epub 2021 Sep 28.

Institute of Molecular and Cellular Biology, A*STAR, Singapore, Singapore.

Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-25583-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479069PMC
September 2021

Estrogen and COVID-19 symptoms: Associations in women from the COVID Symptom Study.

PLoS One 2021 10;16(9):e0257051. Epub 2021 Sep 10.

Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.

It has been widely observed that adult men of all ages are at higher risk of developing serious complications from COVID-19 when compared with women. This study aimed to investigate the association of COVID-19 positivity and severity with estrogen exposure in women, in a population based matched cohort study of female users of the COVID Symptom Study application in the UK. Analyses included 152,637 women for menopausal status, 295,689 women for exogenous estrogen intake in the form of the combined oral contraceptive pill (COCP), and 151,193 menopausal women for hormone replacement therapy (HRT). Data were collected using the COVID Symptom Study in May-June 2020. Analyses investigated associations between predicted or tested COVID-19 status and menopausal status, COCP use, and HRT use, adjusting for age, smoking and BMI, with follow-up age sensitivity analysis, and validation in a subset of participants from the TwinsUK cohort. Menopausal women had higher rates of predicted COVID-19 (P = 0.003). COCP-users had lower rates of predicted COVID-19 (P = 8.03E-05), with reduction in hospital attendance (P = 0.023). Menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P = 2.22E-05) for HRT users alone. The findings support a protective effect of estrogen exposure on COVID-19, based on positive association between predicted COVID-19 with menopausal status, and negative association with COCP use. HRT use was positively associated with COVID-19, but the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential unaccounted for confounders and comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257051PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432854PMC
September 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 09 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612069PMC
September 2021

Childhood growth and development and DNA methylation age in mid-life.

Clin Epigenetics 2021 08 9;13(1):155. Epub 2021 Aug 9.

CLOSER, UCL Institute of Education, University College London, London, WC1H 0NU, UK.

Background: In the first study of its kind, we examine the association between growth and development in early life and DNAm age biomarkers in mid-life.

Methods: Participants were from the Medical Research Council National Survey of Health and Development (n = 1376). Four DNAm age acceleration (AgeAccel) biomarkers were measured when participants were aged 53 years: AgeAccelHannum; AgeAccelHorvath; AgeAccelLevine; and AgeAccelGrim. Exposure variables included: relative weight gain (standardised residuals from models of current weight z-score on current height, and previous weight and height z-scores); and linear growth (standardised residuals from models of current height z-score on previous height and weight z-scores) during infancy (0-2 years, weight gain only), early childhood (2-4 years), middle childhood (4-7 years) and late childhood to adolescence (7-15 years); age at menarche; and pubertal stage for men at 14-15 years. The relationship between relative weight gain and linear growth and AgeAccel was investigated using conditional growth models. We replicated analyses from the late childhood to adolescence period and pubertal timing among 240 participants from The National Child and Development Study (NCDS).

Results: A 1SD increase in relative weight gain in late childhood to adolescence was associated with 0.50 years (95% CI 0.20, 0.79) higher AgeAccelGrim. Although the CI includes the null, the estimate was similar in NCDS [0.57 years (95% CI - 0.01, 1.16)] There was no strong evidence that relative weight gain and linear growth in childhood was associated with any other AgeAccel biomarker. There was no relationship between pubertal timing in men and AgeAccel biomarkers. Women who reached menarche ≥ 12 years had 1.20 years (95% CI 0.15, 2.24) higher AgeAccelGrim on average than women who reached menarche < 12 years; however, this was not replicated in NCDS and was not statistically significant after Bonferroni correction.

Conclusions: Our findings generally do not support an association between growth and AgeAccel biomarkers in mid-life. However, we found rapid weight gain during pubertal development, previously related to higher cardiovascular disease risk, to be associated with older AgeAccelGrim. Given this is an exploratory study, this finding requires replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-021-01138-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351141PMC
August 2021

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.

Nat Commun 2021 05 14;12(1):2830. Epub 2021 May 14.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121846PMC
May 2021

Revisiting the Impact of Local Leptin Signaling in Folliculogenesis and Oocyte Maturation in Obese Mothers.

Int J Mol Sci 2021 Apr 20;22(8). Epub 2021 Apr 20.

Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of PAS, Tuwima 10, 10-748 Olsztyn, Poland.

The complex nature of folliculogenesis regulation accounts for its susceptibility to maternal physiological fitness. In obese mothers, progressive expansion of adipose tissue culminates with severe hyperestrogenism and hyperleptinemia with detrimental effects for ovarian performance. Indeed, maternal obesity is associated with the establishment of ovarian leptin resistance. This review summarizes current knowledge on potential effects of impaired leptin signaling throughout folliculogenesis and oocyte developmental competence in mice and women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22084270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074257PMC
April 2021

Life course socioeconomic position and DNA methylation age acceleration in mid-life.

J Epidemiol Community Health 2021 11 27;75(11):1084-1090. Epub 2021 Apr 27.

MRC Unit for Lifelong Health and Ageing, Faculty of Population Health, UCL, London, UK.

Background: Ageing biomarkers can help us better understand how well-established socioeconomic position (SEP) disparities in ageing occur. A promising new set of DNAm methylation (DNAm)-based ageing biomarkers indicate through their age acceleration (AA) measures if biological ageing is slower or faster than chronological ageing. Few studies have investigated the association between SEP and DNAm AA.

Methods: We used linear regression to examine the sex-adjusted relationships between childhood social class, adult social class, intergenerational social class change, education and adult household earnings with first (Horvath AA and Hannum AA) and second generation (PhenoAge AA and GrimAge AA) DNAm AA markers using data from the MRC National Survey of Health and Development.

Results: In the first-generation biomarkers, there was little evidence of any associations with Horvath AA but associations of childhood social class and income with Hannum AA were observed. Strong associations were seen between greater disadvantage in childhood and adult SEP and greater AA in the second generation biomarkers. For example, those with fathers in an unskilled occupational social class in childhood had 3.6 years greater PhenoAge AA (95% CI 1.8 to 5.4) than those with fathers from a professional social class. Individuals without qualifications had higher AA compared with those with higher education (4.1 years greater GrimAge AA (95% CI 3.1 to 5.0)).

Conclusion: Our findings highlight the importance of exposure to social disadvantage in childhood to the biological ageing process. The second generation clocks appear to be more sensitive to the accumulation of social disadvantage across the life course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jech-2020-215608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515099PMC
November 2021

Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L.

J Clin Endocrinol Metab 2021 04;106(5):e2191-e2202

Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.

Context: Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited.

Objective: To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.

Method: We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed.

Results: We identified 2 DMPs with epigenome-wide significant (P < 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E-10) and cg04173586 in DOT1L (P = 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH.

Conclusions: This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063248PMC
April 2021

Identification of a unique epigenetic profile in women with diminished ovarian reserve.

Fertil Steril 2021 03 4;115(3):732-741. Epub 2020 Dec 4.

Department of Obstetrics and Gynaecology, Department of Reproductive Medicine, Hospital Herlev, Copenhagen University, Copenhagen, Denmark.

Objective: To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve.

Design: Prospectively collected material from a multicenter cohort of women undergoing fertility treatment.

Setting: Private and university-based facilities for clinical services and research.

Patient(s): One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC.

Intervention(s): None.

Main Outcome Measure(s): Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations.

Result(s): Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485).

Conclusion(s): The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fertnstert.2020.09.009DOI Listing
March 2021

Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis.

Aging Cell 2020 12 17;19(12):e13278. Epub 2020 Nov 17.

Epigenetics Programme, Babraham Institute, Cambridge, UK.

Advancing maternal age causes a progressive reduction in fertility. The decline in developmental competence of the oocyte with age is likely to be a consequence of multiple contributory factors. Loss of epigenetic quality of the oocyte could impair early developmental events or programme adverse outcomes in offspring that manifest only later in life. Here, we undertake joint profiling of the transcriptome and DNA methylome of individual oocytes from reproductively young and old mice undergoing natural ovulation. We find reduced complexity as well as increased variance in the transcriptome of oocytes from aged females. This transcriptome heterogeneity is reflected in the identification of discrete sub-populations. Oocytes with a transcriptome characteristic of immature chromatin configuration (NSN) clustered into two groups: one with reduced developmental competence, as indicated by lower expression of maternal effect genes, and one with a young-like transcriptome. Oocytes from older females had on average reduced CpG methylation, but the characteristic bimodal methylation landscape of the oocyte was preserved. Germline differentially methylated regions of imprinted genes were appropriately methylated irrespective of age. For the majority of differentially expressed transcripts, the absence of correlated methylation changes suggests a post-transcriptional basis for most age-related effects on the transcriptome. However, we did find differences in gene body methylation at which there were corresponding changes in gene expression, indicating age-related effects on transcription that translate into methylation differences. Interestingly, oocytes varied in expression and methylation of these genes, which could contribute to variable competence of oocytes or penetrance of maternal age-related phenotypes in offspring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744954PMC
December 2020

Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis.

Cancers (Basel) 2020 Sep 22;12(9). Epub 2020 Sep 22.

Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile.

Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis. Genome-wide methylation sequencing of paired samples of colon (normal adjacent, primary tumour and lymph node metastasis) showed global hypomethylation and CpG island (CGI) hypermethylation of primary tumours compared to normal. In metastasis we observed high global and non-CGI regions methylation, but lower CGI methylation, compared to primary tumours. Gene ontology analysis showed shared biological processes between hypermethylated CGIs in metastasis and primary tumours. After complementary analysis with The Cancer Genome Atlas (TCGA) cohort, , , , and genes were found associated with poor survival. We mapped the methylation landscape of colon normal tissues, primary tumours and lymph node metastasis, being capable of identified methylation changes throughout the genome. Furthermore, we found five genes with potential for methylation biomarkers of poor prognosis in colorectal cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564781PMC
September 2020

Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.

Aging (Albany NY) 2020 07 22;12(14):14092-14124. Epub 2020 Jul 22.

Section General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02215, USA.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality ( < 9.3x10) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to , and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to , and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes () linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425458PMC
July 2020

Leptin Resistance in the Ovary of Obese Mice is Associated with Profound Changes in the Transcriptome of Cumulus Cells.

Cell Physiol Biochem 2020 Apr;54(3):417-437

Institute of Animal Reproduction and Food Research of PAS, Department of Reproductive Immunology and Pathology, Olsztyn, Poland,

Background/aims: Obesity is associated with infertility, decreased ovarian performance and lipotoxicity. However, little is known about the aetiology of these reproductive impairments. Here, we hypothesise that the majority of changes in ovarian physiology in diet-induced obesity (DIO) are a consequence of transcriptional changes downstream of altered leptin signalling. Therefore, we investigated the extent to which leptin signalling is altered in the ovary upon obesity with particular emphasis on effects on cumulus cells (CCs), the intimate functional companions of the oocyte. Furthermore, we used the pharmacological hyperleptinemic (LEPT) mouse model to compare transcriptional profiles to DIO.

Methods: Mice were subjected to DIO for 4 and 16 weeks (wk) and leptin treatment for 16 days, to study effects in the ovary in components of leptin signalling at the transcript and protein levels, using Western blot, Real-time PCR and immunostaining. Furthermore, we used low-cell RNA sequencing to characterise changes in the transcriptome of CCs in these models.

Results: In the DIO model, obesity led to establishment of ovarian leptin resistance after 16 wk high fat diet (HFD), as evidenced by increases in the feedback regulator suppressor of cytokine signalling 3 (SOCS3) and decreases in the positive effectors phosphorylation of tyrosine 985 of leptin receptor (ObRb-pTyr985) and Janus kinase 2 (pJAK2). Transcriptome analysis of the CCs revealed a complex response to DIO, with large numbers and distinct sets of genes deregulated at early and late stages of obesity; in addition, there was a striking correlation between body weight and global transcriptome profile of CCs. Further analysis indicated that the transcriptome profile in 4 wk HFD CCs resembled that of LEPT CCs, in the upregulation of cellular trafficking and impairment in cytoskeleton organisation. Conversely, after 16 wk HFD CCs showed expression changes indicative of augmented inflammatory responses, cell morphogenesis, and decreased metabolism and transport, mainly as a consequence of the physiological changes of obesity.

Conclusion: Obesity leads to ovarian leptin resistance and major time-dependent changes in gene expression in CCs, which in early obesity may be caused by increased leptin signalling in the ovary, whereas in late obesity are likely to be a consequence of metabolic changes taking place in the obese mother.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.33594/000000228DOI Listing
April 2020

DNA Methylation Age and Physical and Cognitive Aging.

J Gerontol A Biol Sci Med Sci 2020 02;75(3):504-511

MRC Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Science, University College London, UK.

Background: DNA methylation (DNAm) age acceleration (AgeAccel) has been shown to be predictive of all-cause mortality but it is unclear what functional aspect(s) of aging it captures. We examine associations between four measures of AgeAccel in adults aged 45-87 years and physical and cognitive performance and their age-related decline.

Methods: AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno, and AgeAccelGrim were calculated in the Medical Research Council National Survey of Health and Development (NSHD), National Child Development Study (NCDS) and TwinsUK. Three measures of physical (grip strength, chair rise speed, and forced expiratory volume in one second [FEV1]) and two measures of cognitive (episodic memory and mental speed) performance were assessed.

Results: AgeAccelPheno and AgeAccelGrim, but not AgeAccelHannum and AgeAccelHorvath were related to performance in random effects meta-analyses (n = 1,388-1,685). For example, a 1-year increase in AgeAccelPheno or AgeAccelGrim was associated with a 0.01 mL (95% confidence interval [CI]: 0.01, 0.02) or 0.03 mL (95% CI: 0.01, 0.05) lower mean FEV1 respectively. In NSHD, AgeAccelPheno and AgeAccelGrim at 53 years were associated with age-related decline in performance between 53 and 69 years as tested by linear mixed models (p < .05). In a subset of NSHD participants (n = 482), there was little evidence that change in any AgeAccel measure was associated with change in performance conditional on baseline performance.

Conclusions: We found little evidence to support associations between the first generation of DNAm-based biomarkers of aging and age-related physical or cognitive performance in midlife to early old age. However, there was evidence that the second generation biomarkers, AgeAccelPheno and AgeAccelGrim, could act as makers of an individual's healthspan as proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glz246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414926PMC
February 2020

Dissecting the role of the gut microbiota and diet on visceral fat mass accumulation.

Sci Rep 2019 07 5;9(1):9758. Epub 2019 Jul 5.

The Department of Twin Research and Genetic Epidemiology, Kings College London, 3-4th Floor South Wing Block D, St Thomas' Hospital, Westminster Bridge Road, SE1 7E, London, UK.

Both gut microbiota and diet have been shown to impact visceral fat mass (VFM), a major risk factor for cardiometabolic disease, but their relative contribution has not been well characterised. We aimed to estimate and separate the effect of gut microbiota composition from that of nutrient intake on VFM in 1760 older female twins. Through pairwise association analyses, we identified 93 operational taxonomic units (OTUs) and 10 nutrients independently linked to VFM (FDR < 5%). Conditional analyses revealed that the majority (87%) of the 93 VFM-associated OTUs remained significantly associated with VFM irrespective of nutrient intake correction. In contrast, we observed that the effect of fibre, magnesium, biotin and vitamin E on VFM was partially mediated by OTUs. Moreover, we estimated that OTUs were more accurate predictors of VFM than nutrients and accounted for a larger percentage of its variance. Our results suggest that while the role of certain nutrients on VFM appears to depend on gut microbiota composition, specific gut microbes may affect host adiposity regardless of dietary intake. The findings imply that the gut microbiota may have a greater contribution towards shaping host VFM than diet alone. Thus, microbial-based therapy should be prioritised for VFM reduction in overweight and obese subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46193-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611773PMC
July 2019

Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals.

Am J Clin Nutr 2019 08;110(2):437-450

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.

Background: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans.

Objective: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes.

Methods: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes.

Results: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs.

Conclusions: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqz031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669135PMC
August 2019

Epigenetic findings in periodontitis in UK twins: a cross-sectional study.

Clin Epigenetics 2019 02 13;11(1):27. Epub 2019 Feb 13.

Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London, UK.

Background: Genetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease.

Methods: Self-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples.

Results: Epigenome-wide analyses in blood identified one CpG-site (cg21245277 in ZNF804A) associated with gingival bleeding (FDR = 0.03, nominal p value = 7.17e-8) and 58 sites associated with tooth mobility (FDR < 0.05) with the top signals in IQCE and XKR6. Epigenetic variation at 28 candidate regions (247 CpG-sites) for chronic periodontitis showed an enrichment for association with periodontal traits, and signals in eight genes (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, and CXCL1) were significant in both traits. The methylation-phenotype association signals validated in buccal samples, and a subset (25%) also validated in adipose tissue.

Conclusions: Epigenome-wide analyses in adult female twins identified specific DNA methylation changes linked to self-reported periodontal disease. Future work will explore the environmental basis and functional impact of these results to infer potential for strategic personalized treatments and prevention of chronic periodontitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0614-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375219PMC
February 2019

Smoking induces coordinated DNA methylation and gene expression changes in adipose tissue with consequences for metabolic health.

Clin Epigenetics 2018 10 20;10(1):126. Epub 2018 Oct 20.

Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.

Background: Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear.

Methods: We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat.

Results: We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation.

Conclusions: Our results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-018-0558-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196025PMC
October 2018

Genome-wide methylation analysis identifies ELOVL5 as an epigenetic biomarker for the risk of type 2 diabetes mellitus.

Sci Rep 2018 10 5;8(1):14862. Epub 2018 Oct 5.

Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Republic of Korea.

Genome-wide DNA methylation has been implicated in complex human diseases. Here, we identified epigenetic biomarkers for type 2 diabetes (T2D) underlying obesogenic environments. In a blood-based DNA methylation analysis of 11 monozygotic twins (MZTW) discordant for T2D, we discovered genetically independent candidate methylation sites. In a follow-up replication study (17 MZTW pairs) for external validation, we replicated the T2D-association at a novel CpG signal in the ELOVL fatty acid elongase 5 (ELOVL5) gene specific to T2D-discordant MZTW. For concordant DNA methylation signatures in tissues, we further confirmed that a CpG site (cg18681426) was associated with adipogenic differentiation between human preadipocytes and adipocytes isolated from the same biopsy sample. In addition, the ELOVL5 gene was significantly differentially expressed in adipose tissues from unrelated T2D patients and in human pancreatic islets. Our results demonstrate that blood-derived DNA methylation is associated with T2D risk as a proxy for cumulative epigenetic status in human adipose and pancreatic tissues. Moreover, ELOVL5 expression was increased in cellular and mouse models of induced obesity-related diabetes. These findings may provide new insights into epigenetic architecture by uncovering methylation-based biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-33238-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173741PMC
October 2018

Associations between body size, nutrition and socioeconomic position in early life and the epigenome: A systematic review.

PLoS One 2018 10;13(8):e0201672. Epub 2018 Aug 10.

MRC Unit for Lifelong Health and Ageing, Institute of Cardiovascular Science, University College London, London, United Kingdom.

Background: Body size, nutrition and socioeconomic position (SEP) in early life have been associated with a wide range of long-term health effects. Epigenetics is one possible mechanism through which these early life exposures can impact later life health. We conducted a systematic review examining the observational evidence for the impact of body size, nutrition and SEP in early life on the epigenome in humans.

Methods: This systematic review is registered with the PROSPERO database (registration number: CRD42016050193). Three datasets were simultaneously searched using Ovid and the resulting studies were evaluated by at least two independent reviewers. Studies measuring epigenetic markers either at the same time as, or after, the early life exposure and have a measure of body size, nutrition or SEP in early life (up to 12 years), written in English and from a community-dwelling participants were included.

Results: We identified 90 eligible studies. Seventeen of these papers examined more than one early life exposure of interest. Fifty six papers examined body size, 37 nutrition and 17 SEP. All of the included papers examined DNA methylation (DNAm) as the epigenetic marker. Overall there was no strong evidence for a consistent association between these early life variables in DNAm which may be due to the heterogeneous study designs, data collection methods and statistical analyses.

Conclusions: Despite these inconclusive results, the hypothesis that the early life environment can impact DNAm, potentially persisting into adult life, was supported by some studies and warrants further investigation. We provide recommendations for future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201672PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086410PMC
January 2019

A computational toxicogenomics approach identifies a list of highly hepatotoxic compounds from a large microarray database.

PLoS One 2017 27;12(4):e0176284. Epub 2017 Apr 27.

Computational Genomics Lab., Instituto Nacional de Medicina Genómica, Mexico City, México.

The liver and the kidney are the most common targets of chemical toxicity, due to their major metabolic and excretory functions. However, since the liver is directly involved in biotransformation, compounds in many currently and normally used drugs could affect it adversely. Most chemical compounds are already labeled according to FDA-approved labels using DILI-concern scale. Drug Induced Liver Injury (DILI) scale refers to an adverse drug reaction. Many compounds do not exhibit hepatotoxicity at early stages of development, so it is important to detect anomalies at gene expression level that could predict adverse reactions in later stages. In this study, a large collection of microarray data is used to investigate gene expression changes associated with hepatotoxicity. Using TG-GATEs a large-scale toxicogenomics database, we present a computational strategy to classify compounds by toxicity levels in human and animal models through patterns of gene expression. We combined machine learning algorithms with time series analysis to identify genes capable of classifying compounds by FDA-approved labeling as DILI-concern toxic. The goal is to define gene expression profiles capable of distinguishing the different subtypes of hepatotoxicity. The study illustrates that expression profiling can be used to classify compounds according to different hepatotoxic levels; to label those that are currently labeled as undertemined; and to determine if at the molecular level, animal models are a good proxy to predict hepatotoxicity in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176284PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407788PMC
September 2017

Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density.

J Bone Miner Res 2017 Aug 8;32(8):1644-1650. Epub 2017 May 8.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome-wide association study (EWAS) of BMD. We undertook a large-scale BMD EWAS using the Infinium HumanMethylation450 array to measure site-specific DNA methylation in up to 5515 European-descent individuals (N = 4614, N = 901). We associated methylation at multiple cytosine-phosphate-guanine (CpG) sites with dual-energy X-ray absorptiometry (DXA)-derived femoral neck and lumbar spine BMD. We performed sex-combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false-discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females (p = 7.9 × 10 ) and 4614 females and males (p = 3.0 × 10 ). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females (p = 0.64) and 901 males and females (p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large-effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage. © 2017 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615229PMC
August 2017

DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation.

Genome Med 2017 03 24;9(1):28. Epub 2017 Mar 24.

Department of Twin Research and Genetic Epidemiology, King's College London, SE1 7EH, London, UK.

Background: The association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome.

Methods: We investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing.

Results: At a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental factors appear to be the main overall contributors of methylation variability at the FDR 25% IVF-associated differentially methylated regions, although evidence for methylation heritability was also obtained at several of these regions. We replicated previous findings of differential methylation associated with IVF at the H19/IGF2 region in cord blood mononuclear cells, and we validated the signal at C9orf3 in monozygotic twins. We also explored the impact of intracytoplasmic sperm injection on the FDR 25% signals for potential effects specific to male or female infertility factors.

Conclusions: To our knowledge, this is the most comprehensive study of DNA methylation profiles at birth and IVF conception to date, and our results show evidence for epigenetic modifications that may in part reflect parental subfertility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-017-0413-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364659PMC
March 2017

Down-Regulation of TLR and JAK/STAT Pathway Genes Is Associated with Diffuse Cutaneous Leishmaniasis: A Gene Expression Analysis in NK Cells from Patients Infected with Leishmania mexicana.

PLoS Negl Trop Dis 2016 Mar 31;10(3):e0004570. Epub 2016 Mar 31.

Unidad de Investigación en Medicina Experimental, Centro de Medicina Tropical, Facultad de Medicina, Universidad Nacional Autónoma de México, Avenida, D.F., México.

An important NK-cell inhibition with reduced TNF-α, IFN-γ and TLR2 expression had previously been identified in patients with diffuse cutaneous leishmaniasis (DCL) infected with Leishmania mexicana. In an attempt to pinpoint alterations in the signaling pathways responsible for the NK-cell dysfunction in patients with DCL, this study aimed at identifying differences in the NK-cell response towards Leishmania mexicana lipophosphoglycan (LPG) between patients with localized and diffuse cutaneous leishmaniasis through gene expression profiling. Our results indicate that important genes involved in the innate immune response to Leishmania are down-regulated in NK cells from DCL patients, particularly TLR and JAK/STAT signaling pathways. This down-regulation showed to be independent of LPG stimulation. The study sheds new light for understanding the mechanisms that undermine the correct effector functions of NK cells in patients with diffuse cutaneous leishmaniasis contributing to a better understanding of the pathobiology of leishmaniasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0004570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816531PMC
March 2016

Genetic and environmental impacts on DNA methylation levels in twins.

Epigenomics 2016 Jan 18;8(1):105-17. Epub 2015 Dec 18.

Department of Twin Research & Genetic Epidemiology, King's College, London, UK.

Epigenetics describes the study of cellular modifications that can modify the expression of genes without changing the DNA sequence. DNA methylation is one of the most stable and prevalent epigenetic mechanisms. Twin studies have been a valuable model for unraveling the genetic and epigenetic epidemiology of complex traits, and now offer a potential to dissect the factors that impact DNA methylation variability and its biomedical significance. The twin design specifically allows for the study of genetic, environmental and lifestyle factors, and their potential interactions, on epigenetic profiles. Furthermore, genetically identical twins offer a unique opportunity to assess nongenetic impacts on epigenetic profiles. Here, we summarize recent findings from twin studies of DNA methylation profiles across tissues, to define current knowledge regarding the genetic and nongenetic factors that influence epigenetic variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi.15.90DOI Listing
January 2016

Epigenetics of discordant monozygotic twins: implications for disease.

Genome Med 2014 31;6(7):60. Epub 2014 Jul 31.

Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH UK.

Monozygotic (MZ) twins share nearly all of their genetic variants and many similar environments before and after birth. However, they can also show phenotypic discordance for a wide range of traits. Differences at the epigenetic level may account for such discordances. It is well established that epigenetic states can contribute to phenotypic variation, including disease. Epigenetic states are dynamic and potentially reversible marks involved in gene regulation, which can be influenced by genetics, environment, and stochastic events. Here, we review advances in epigenetic studies of discordant MZ twins, focusing on disease. The study of epigenetics and disease using discordant MZ twins offers the opportunity to control for many potential confounders encountered in general population studies, such as differences in genetic background, early-life environmental exposure, age, gender, and cohort effects. Recently, analysis of disease-discordant MZ twins has been successfully used to study epigenetic mechanisms in aging, cancer, autoimmune disease, psychiatric, neurological, and multiple other traits. Epigenetic aberrations have been found in a range of phenotypes, and challenges have been identified, including sampling time, tissue specificity, validation, and replication. The results have relevance for personalized medicine approaches, including the identification of prognostic, diagnostic, and therapeutic targets. The findings also help to identify epigenetic markers of environmental risk and molecular mechanisms involved in disease and disease progression, which have implications both for understanding disease and for future medical research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-014-0060-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254430PMC
December 2014
-->