Analysis of genome-wide DNA methylation patterns in obesity

Chun-hu, Wang; Wang, Meng; Ma, Jiguang

doi:10.1507/endocrj.ej20-0734

Cited by 8 publications

(6 citation statements)

References 42 publications

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“…Calcium signaling could be involved in the neural control of hunger and energy metabolism as well as in the gut–brain axis [ 52 , 53 ]. In line with our study, another genome-wide DNA methylome study conducted on people with obesity reported calcium-signaling among the top five enriched pathways [ 54 ].…”

Section: Discussionsupporting

confidence: 89%

Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals

et al. 2022

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Background Obesity is a multifactorial and chronic condition of growing universal concern. It has recently been reported that bariatric surgery is a more successful treatment for severe obesity than other noninvasive interventions, resulting in rapid significant weight loss and associated chronic disease remission. The identification of distinct epigenetic patterns in patients who are obese or have metabolic imbalances has suggested a potential role for epigenetic alterations in causal or mediating pathways in the development of obesity-related pathologies. Specific changes in the epigenome (DNA methylome), associated with metabolic disorders, can be detected in the blood. We investigated whether such epigenetic changes are reversible after weight loss using genome-wide DNA methylome analysis of blood samples from individuals with severe obesity (mean BMI ~ 45) undergoing bariatric surgery. Results Our analysis revealed 41 significant (Bonferroni p < 0.05) and 1169 (false discovery rate p < 0.05) suggestive differentially methylated positions (DMPs) associated with weight loss due to bariatric surgery. Among the 41 significant DMPs, 5 CpGs were replicated in an independent cohort of BMI-discordant monozygotic twins (the heavier twin underwent diet-induced weight loss). The effect sizes of these 5 CpGs were consistent across discovery and replication sets (p < 0.05). We also identified 192 differentially methylated regions (DMRs) among which SMAD6 and PFKFB3 genes were the top hypermethylated and hypomethylated regions, respectively. Pathway enrichment analysis of the DMR-associated genes showed that functional pathways related to immune function and type 1 diabetes were significant. Weight loss due to bariatric surgery also significantly decelerated epigenetic age 12 months after the intervention (mean = − 4.29; p = 0.02). Conclusions We identified weight loss-associated DNA-methylation alterations targeting immune and inflammatory gene pathways in blood samples from bariatric-surgery patients. The top hits were replicated in samples from an independent cohort of BMI-discordant monozygotic twins following a hypocaloric diet. Energy restriction and bariatric surgery thus share CpGs that may represent early indicators of response to the metabolic effects of weight loss. The analysis of bariatric surgery-associated DMRs suggests that epigenetic regulation of genes involved in endothelial and adipose tissue function is key in the pathophysiology of obesity.

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Section: Discussionsupporting

confidence: 89%

Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals

et al. 2022

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“…In this study, we found that the differential methylation signal of SOSTDC1 gene was ranked at the top, and combined with the expression characteristics of SOSTDC1 gene, we suggest that differential methylation of SOSTDC1 is the main reason for differential expression of the SOSTDC1 gene, and consequently the formation of the ALC wool type. Indeed, in the studies related to genome-wide methylation analysis to date, the significantly differential methylation sites tend to be scattered across chromosomes [ 52 – 55 ], however, in this study, the differentially methylated sites were concentrated in one gene and the signals were much more significant than other sites in the genome. This result is most likely due to three reasons: first, the samples tested are siblings with a relatively consistent genetic background, second, the target characteristics are distinctly different and the time points and body parts where the samples were collected are precisely consistent among individuals, and finally, there does exist a CpG island on the second exon of sheep SOSTDC1 gene (Fig.…”

Section: Discussioncontrasting

confidence: 53%

Genome-wide DNA methylation and transcriptome analyses reveal the key gene for wool type variation in sheep

Wang

Hua

Cai

et al. 2023

J Animal Sci Biotechnol

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Background Wool fibers are valuable materials for textile industry. Typical wool fibers are divided into medullated and non-medullated types, with the former generated from primary wool follicles and the latter by either primary or secondary wool follicles. The medullated wool is a common wool type in the ancestors of fine wool sheep before breeding. The fine wool sheep have a non-medullated coat. However, the critical period determining the type of wool follicles is the embryonic stage, which limits the phenotypic observation and variant contrast, making both selection and studies of wool type variation fairly difficult. Results During the breeding of a modern fine (MF) wool sheep population with multiple-ovulation and embryo transfer technique, we serendipitously discovered lambs with ancestral-like coarse (ALC) wool. Whole-genome resequencing confirmed ALC wool lambs as a variant type from the MF wool population. We mapped the significantly associated methylation locus on chromosome 4 by using whole genome bisulfite sequencing signals, and in turn identified the SOSTDC1 gene as exons hypermethylated in ALC wool lambs compare to their half/full sibling MF wool lambs. Transcriptome sequencing found that SOSTDC1 was expressed dozens of times more in ALC wool lamb skin than that of MF and was at the top of all differentially expressed genes. An analogy with the transcriptome of coarse/fine wool breeds revealed that differentially expressed genes and enriched pathways at postnatal lamb stage in ALC/MF were highly similar to those at the embryonic stage in the former. Further experiments validated that the SOSTDC1 gene was specifically highly expressed in the nucleus of the dermal papilla of primary wool follicles. Conclusion In this study, we conducted genome-wide differential methylation site association analysis on differential wool type trait, and located the only CpG locus that strongly associated with primary wool follicle development. Combined with transcriptome analysis, SOSTDC1 was identified as the only gene at this locus that was specifically overexpressed in the primary wool follicle stem cells of ALC wool lamb skin. The discovery of this key gene and its epigenetic regulation contributes to understanding the domestication and breeding of fine wool sheep.

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“…Hence, we concentrated only on the CpG sites with an absolute mean β difference > 0.1 (Table 1). Interestingly, several of these ethnically differentiated sites were previously reported for their association with common diseases, for instance, cg09789536 for cow's milk allergy [40], cg07157834 and cg25629442 for Alzheimer's disease [41,42], cg09894276 for obesity [43], and cg04635334 for depression [44]. Moreover, 9 of the 23 CpG sites had a cis or trans methylation quantitative trait loci [45], suggesting that genome variation plays a non-negligible role in shaping ethnic differences in DNA methylation pattern among closely related populations, as previously validated in inter-continental human populations.…”

Section: Differences In Genome-wide Dna Methylation Levels At the Cpg...mentioning

confidence: 99%

Genome-wide DNA methylation status of Mongolians exhibits signs of cellular stress response related to their nomadic lifestyle

Inaba

Iwamoto

Nakayama

2022

J Physiol Anthropol

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Background Epigenetics is crucial for connecting environmental stresses with physiological responses in humans. Mongolia, where nomadic livestock pastoralism has been the primal livelihood, has a higher prevalence of various chronic diseases than the surrounding East Asian regions, which are more suitable for crop farming. The genes related to dietary stress and pathogenesis of related disorders may have varying epigenetic statuses among the human populations with diverse dietary cultures. Hence, to understand such epigenetic differences, we conducted a comparative analysis of genome-wide DNA methylation of Mongolians and crop-farming East Asians. Methods Genome-wide DNA methylation status of peripheral blood cells (PBCs) from 23 Mongolian adults and 24 Thai adults was determined using the Infinium Human Methylation 450K arrays and analyzed in combination with previously published 450K data of 20 Japanese and 8 Chinese adults. CpG sites/regions differentially methylated between Mongolians and crop-farming East Asians were detected using a linear model adjusted for sex, age, ethnicity, and immune cell heterogeneity on RnBeads software. Results Of the quality-controlled 389,454 autosomal CpG sites, 223 CpG sites were significantly differentially methylated among Mongolians and the four crop farming East Asian populations (false discovery rate < 0.05). Analyses focused on gene promoter regions revealed that PM20D1 (peptidase M20 domain containing 1), which is involved in mitochondrial uncoupling and various processes, including cellular protection from reactive oxygen species (ROS) and thermogenesis, was the top differentially methylated gene. Moreover, gene ontology enrichment analysis revealed that biological processes related to ROS metabolism were overrepresented among the top 1% differentially methylated genes. The promoter regions of these genes were generally hypermethylated in Mongolians, suggesting that the metabolic pathway detoxifying ROS might be globally suppressed in Mongolians, resulting in the high susceptibility of this population to various chronic diseases. Conclusions This study showed a significantly diverse DNA methylation status among Mongolians and crop-farming East Asians. Further, we found an association between the differentially methylated genes and various metabolic and neurodegenerative diseases. Knowledge of the epigenetic regulators might help in proper understanding, treatment, and control of such disorders, and physiological adaptation in the future.

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Analysis of genome-wide DNA methylation patterns in obesity

Cited by 8 publications

References 42 publications

Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals

Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals

Genome-wide DNA methylation and transcriptome analyses reveal the key gene for wool type variation in sheep

Genome-wide DNA methylation status of Mongolians exhibits signs of cellular stress response related to their nomadic lifestyle

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