Effect of different iodine levels on the DNA methylation of PRKAA2, ITGA6, THEM4 and PRL genes in PI3K-AKT signaling pathway and population-based validation from autoimmune thyroiditis patients

Ren, Bingxuan; Wan, Siyuan; Wu, Hui; Qu, Mengying; Chen, Yao; Liu, Lixiang; Jin, Meihui; Zhou, Zheng; Shen, Hongmei

doi:10.1007/s00394-022-02907-x

Cited by 9 publications

(5 citation statements)

References 36 publications

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“…One study in the elderly showed that iodine could not modulate the global DNA methylation profile of leukocytes (43) , and another study in animals showed that IE did not change the global methylation levels in lymphocytes (44) . Our previous studies have shown that different iodine levels could affect the methylation patterns of DAPK1 and ITGA6 (45,46) . This study further confirms that iodine status could affect the methylation levels of intrinsic apoptosis genes.…”

Section: Discussionmentioning

confidence: 99%

Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene–environment interactions in patients with autoimmune thyroiditis

Zhou

Jin

et al. 2023

Br J Nutr

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Iodine, is an essential nutrient that may change the occurrence of autoimmune thyroiditis (AIT). Apoptosis and DNA methylation participate in the pathogenesis and destructive mechanism of AIT. We detected the methylation and the expression of mRNA of intrinsic apoptosis-associated genes (YWHAG, ING4, BRSK2, and GJA1) to identify the potential interactions between the levels of methylation in these genes and different levels of iodine. 176 adult patients with AIT in Shandong Province, China, were included. The MethylTargetTM assay was used to verify the levels of methylation. We used PCR to detect the mRNA levels of the candidate genes. Interactions between methylation levels of the candidate genes and iodine levels were evaluated with multiplicative and addictive interaction models and GMDR. In the AIT group, YWHAG_1 and six CpG sites, and BRSK2_1 and eight CpG sites were hypermethylated, whereas ING4_1 and one CpG site were hypomethylated. A negative correlation was found between methylation levels of YWHAG and mRNA expression. The combination of iodine fortification, YWHAG_1 hypermethylation, and BRSK2_1 hypermethylation was significantly associated with elevated AIT risk. A four-locus model (YWHAG_1×ING4_1×BRSK2_1×iodine level) was found to be the best model of the gene-environment interactions. We identified abnormal changes in the methylation status of YWHAG, ING4, and BRSK2 in patients with AIT in different iodine levels. Iodine fortification not only affected the methylation levels of YWHAG and BRSK2 but also interacted with the methylation levels of these genes and may ultimately increase the risk of AIT.

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Section: Discussionmentioning

confidence: 99%

Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene–environment interactions in patients with autoimmune thyroiditis

Zhou

Jin

et al. 2023

Br J Nutr

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“…In terms of iodine presence in 5-ISA-fortified lettuce, there is little known about potential effects of iodine on DNA methylation in human cells although iodine affects thyroid function and play a role in thyroid cancer and other thyroid disease [ 23 ]. Nevertheless, iodine excess has been shown to affect DNA methylation of selected genes in blood of patients with autoimmune thyroiditis [ 24 , 25 ]. Hence, potential epigenetic effects of iodine cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

“…It is believed that altered patterns of DNA methylation play a role in the progression of cancer and pathogenesis of other disease [ 16 ]. Interestingly, polyphenols from lettuce, iodine, and salicylic acid were all reported to exert certain epigenetic effects [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Effects of Iodine-Biofortified Lettuce in Human Gastrointestinal Cancer Cells

et al. 2022

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Considering the growing number of cancer cases around the world, natural products from the diet that exhibit potential antitumor properties are of interest. Our previous research demonstrated that fortification with iodine compounds is an effective way to improve the antioxidant potential of lettuce. The purpose of the present study was to evaluate the effect of iodine-biofortified lettuce on antitumor properties in human gastrointestinal cancer cell lines, gastric AGS and colon HT-29. Our results showed that extracts from iodine-biofortified lettuce reduce the viability and proliferation of gastric and colon cancer cells. The extracts mediated cell cycle arrest which was accompanied by inactivation of anti-apoptotic Bcl-2 and activation of caspases, as assessed by flow cytometry. However, extracts from lettuce fortified with organic forms of iodine acted more effectively than extracts from control and KIO3-enriched plants. Using quantitative PCR, we detected the increase in pro-apoptotic genes BAD, BAX and BID in AGS cells whereas up-regulation of cell cycle progression inhibitor CDKN2A and downregulation of pro-proliferative MDM2 in HT-29 cells. Interestingly, lettuce extracts led to down-regulation of pro-survival AKT1 and protooncogenic MDM2, which was consistent for extracts of lettuce fortified with organic form of iodine, 5-ISA, in both cell lines. MDM2 downregulation in HT-29 colon cancer cells was associated with RB1 upregulation upon 5-ISA-fortified lettuce extracts, which provides a link to the epigenetic regulation of tumor suppressor genes by RB/MDM2 pathway. Indeed, SEMA3A tumor suppressor gene was hypomethylated and upregulated in HT-29 cells treated with 5-ISA-fortified lettuce. Control lettuce exerted similar effects on RB/MDM2 pathway and SEMA3A epigenetic activation in HT-29 cells. Our findings suggest that lettuce as well as lettuce fortified with organic form of iodine, 5-ISA, may exert epigenetic anti-cancer effects that can be cancer type-specific.

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“…They have identified that the PRKAA2_3 gene was hypermethylated whereas the ITGA6 gene was hypomethylated in patients [33]. Iodine level (whether excess or supplementation after deficiency) can affect the DNA methylation level in the previously described genes [33]. This suggests there is a potential correlation between iodine levels and autoimmune thyroid diseases like HT, which provides a new study perspective.…”

Section: Hashimoto's Thyroiditismentioning

confidence: 98%

“…Recently, Ren et al did an epigenome-wide association study comparing the methylation level of patients with autoimmune thyroid disease and healthy controls. They have identified that the PRKAA2_3 gene was hypermethylated whereas the ITGA6 gene was hypomethylated in patients [33]. Iodine level (whether excess or supplementation after deficiency) can affect the DNA methylation level in the previously described genes [33].…”

Section: Hashimoto's Thyroiditismentioning

confidence: 99%

Investigation of DNA methylation in autoimmune diseases with genome-wide association analysis

Fan

2023

International Conference on Modern Medicine and Global Health (ICMMGH 2023)

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Effect of different iodine levels on the DNA methylation of PRKAA2, ITGA6, THEM4 and PRL genes in PI3K-AKT signaling pathway and population-based validation from autoimmune thyroiditis patients

Cited by 9 publications

References 36 publications

Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene–environment interactions in patients with autoimmune thyroiditis

Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene–environment interactions in patients with autoimmune thyroiditis

Molecular Effects of Iodine-Biofortified Lettuce in Human Gastrointestinal Cancer Cells

Investigation of DNA methylation in autoimmune diseases with genome-wide association analysis

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