DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern: a genome-wide analysis from non-obese and obese patients

Crujeiras, Ana B.; Díaz‐Lagares, Ángel; Sandoval, Juan; Milagro, Fermı́n I.; Navas-Carretero, Santiago; Carreira, Marcos C.; Gómez, Antonio; Hervás, David; Monteiro, Mariana P.; Casanueva, Felipe F.; Esteller, Manel; Martínéz, J. Alfredo

doi:10.1038/srep41903

Cited by 91 publications

(82 citation statements)

References 57 publications

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“…According to Tseng 36 , ZFP36L1 overexpression might repress adipogenesis at least by down-regulating PPARG2 expression. These findings are a proof that blood leukocytes are able to reflect the regulation of same adipose tissue biology-related genes as it was also demonstrated in previous reports 13,[37][38][39] . In the current research, we were unable to detect differences in methylation levels of previously identified obesity related CpG sites, probably because differences in the study design, sample size or the threshold used for selection of candidates.…”

Section: Discussionsupporting

confidence: 87%

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Altered pathways in methylome and transcriptome longitudinal analysis of normal weight and bariatric surgery women

Nicoletti

Pinhel

Noronha

et al. 2020

Sci Rep

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DnA methylation could provide a link between environmental, genetic factors and weight control and can modify gene expression pattern. This study aimed to identify genes, which are differentially expressed and methylated depending on adiposity state by evaluating normal weight women and obese women before and after bariatric surgery (BS). We enrolled 24 normal weight (BMI: 22.5 ± 1.6 kg/m 2 ) and 24 obese women (BMI: 43.3 ± 5.7 kg/m 2 ) submitted to BS. Genome-wide methylation analysis was conducted using Infinium Human Methylation 450 BeadChip (threshold for significant CpG sites based on delta methylation level with a minimum value of 5%, a false discovery rate correction (FDR) of q < 0.05 was applied). Expression levels were measured using HumanHT-12v4 Expression BeadChip (cutoff of p ≤ 0.05 and fold change ≥2.0 was used to detect differentially expressed probes). The integrative analysis of both array data identified four genes (i.e. TPP2, PSMG6, ARL6IP1 and FAM49B) with higher methylation and lower expression level in pre-surgery women compared to normal weight women: and two genes (i.e. ZFP36L1 and USP32) that were differentially methylated after BS. These methylation changes were in promoter region and gene body. All genes are related to MAPK cascade, NIK/NF-kappaB signaling, cellular response to insulin stimulus, proteolysis and others. integrating analysis of DnA methylation and gene expression evidenced that there is a set of genes relevant to obesity that changed after BS. A gene ontology analysis showed that these genes were enriched in biological functions related to adipogenesis, orexigenic, oxidative stress and insulin metabolism pathways. Also, our results suggest that although methylation plays a role in gene silencing, the majority of effects were not correlated.DNA methylation in CpG dinucleotides is a dynamic process and best characterized epigenetic modifications 1 . Methylation patterns are established in early life and can be remodeled in adult cells, by modulating DNA interactions with proteins and transcription factors 2,3 , being able to alter gene expression profile 4 .Weight gain or loss during infancy and adulthood, by changing the energy storage and adipose tissue homeostasis, may alter molecular mechanisms and biological processes 5 . In line of this, epigenetic changes may predispose a disease risk or can occur once a disease has developed 6 . Thus, DNA methylation provides a link between environmental, genetic factors and weight control.Obesity has reached epidemic proportions and, in 2016, affected about 1.9 billion adults worldwide 7 , being associated to a public health burden. In the context of obesity treatment, bariatric surgery (BS) has been the best choice for cases of severe obesity and has been shown to be the most effective way to promote significant and sustained weight loss 8 . Among the surgical techniques, Roux-en-Y gastric bypass (RYGB) is the most performed in Brazil and worldwide, and is considered a gold standard because its high efficacy and low morbid-mortalit...

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Section: Discussionsupporting

confidence: 87%

“…However, the current study adds new information to this issue. In fact, the identified genes were involved in adipose tissue-related pathways that were also observed in previous reports on obesity-related methylation profile 13,38,39 .…”

Section: Discussionsupporting

confidence: 84%

Altered pathways in methylome and transcriptome longitudinal analysis of normal weight and bariatric surgery women

Nicoletti

Pinhel

Noronha

et al. 2020

Sci Rep

Self Cite

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“…Although previous studies support tissue‐specific DNA methylation patterns (Lokk et al., 2014), there is growing evidence in humans suggesting that some methylation marks detected in leukocytes can be reflected in other target tissues, including oral mucosa (San‐Cristobal et al., 2016) and subcutaneous adipose tissue (Crujeiras et al., 2017). Also, homologies between genomic signatures (including DNA methylation patterns) from blood and brain were reported in a rodent model of concussive injury (Meng et al., 2017).…”

Section: Discussionmentioning

confidence: 99%

Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake

et al. 2018

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IntroductionDopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features, metabolic profiles, and dietary intake.MethodsAn adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened.ResultsAfter applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p < 0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (CACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the presence or absence of abdominal obesity. Pathway analyses revealed a statistically significant contribution of the aforementioned genes to dopaminergic synapse transmission (p = 4.78E−08). Furthermore, SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p < 0.001) and carbohydrate (p < 0.001) intakes.ConclusionsThe results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition.

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“…Modifications in the gene expression profile observed in hASCs according to the methylation pattern were also explored in PBMCs, as they represent a more accessible source for sampling. Also, epigenetic modifications to hASCs might be reflected in peripheral blood, as already demonstrated in other inflammatory diseases such as obesity [45]. Indeed, changes to the PBMC methylome in CD have previously been described, revealing that differentially methylated genes implicated in immune response are the most frequently affected [19,46].…”

Section: Verification Of Candidate Genes In Circulating Pbmcs In Patimentioning

confidence: 69%

Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

et al. 2020

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Background: Crohn's disease (CD) is characterized by persistent inflammation and ulceration of the small or large bowel, and expansion of mesenteric adipose tissue, termed creeping fat (CF). We previously demonstrated that human adipose-derived stem cells (hASCs) from CF of patients with CD exhibit dysfunctional phenotypes, including a pro-inflammatory profile, high phagocytic capacity, and weak immunosuppressive properties. Importantly, these phenotypes persist in patients in remission and are found in all adipose depots explored including subcutaneous fat. We hypothesized that changes in hASCs are a consequence of epigenetic modifications. Methods: We applied epigenome-wide profiling with a methylation array (Illumina EPIC/850k array) and gene expression analysis to explore the impact of CD on the methylation signature of hASCs isolated from the subcutaneous fat of patients with CD and healthy controls (n = 7 and 5, respectively; cohort I). Differentially methylated positions (p value cutoff < 1 × 10 −4 and ten or more DMPs per gene) and regions (inclusion threshold 0.2, p value cutoff < 1 × 10 −2 and more than 2 DMRs per gene) were identified using dmpfinder and Bumphunter (minfi), respectively. Changes in the expression of differentially methylated genes in hASCs were validated in a second cohort (n = 10/10 inactive and active CD and 10 controls; including patients from cohort I) and also in peripheral blood mononuclear cells (PBMCs) of patients with active/inactive CD and of healthy controls (cohort III; n = 30 independent subjects). Results: We found a distinct DNA methylation landscape in hASCs from patients with CD, leading to changes in the expression of differentially methylated genes involved in immune response, metabolic, cell differentiation, and development processes. Notably, the expression of several of these genes in hASCs and PBMCs such as tumor necrosis factor alpha (TNFA) and PR domain zinc finger protein 16 (PRDM16) were not restored to normal (healthy) levels after disease remission. Conclusions: hASCs of patients with CD exhibit a unique DNA methylation and gene expression profile, but the expression of several genes are only partially restored in patients with inactive CD, both in hASCs and PBMCs. Understanding how CD shapes the functionality of hASCs is critical for investigating the complex pathophysiology of this disease, as well as for the success of cell-based therapies.

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DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern: a genome-wide analysis from non-obese and obese patients

Cited by 91 publications

References 57 publications

Altered pathways in methylome and transcriptome longitudinal analysis of normal weight and bariatric surgery women

Altered pathways in methylome and transcriptome longitudinal analysis of normal weight and bariatric surgery women

Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake

Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

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