Hypermethylation of gene promoters in peripheral blood leukocytes in humans long term after radiation exposure

Кузьмина, Н. С.; Lapteva, N. Sh.; Рубанович, А. В.

doi:10.1016/j.envres.2015.12.008

Cited by 21 publications

(6 citation statements)

References 54 publications

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“…At the gene level, particular loci or even CpG sites have been identified as predictive markers of biological age [ 39 ] and allowed us to identify an increased predicted biological age in cancer survivors. Several components of the radiation response can contribute to accelerated aging or inflammatory diseases, including low-grade systemic inflammation, activation of MAPK/mTOR signaling, epigenetic remodeling, or oxidative stress [ 12 , 33 , 38 , 40 , 41 ]. In the present study, we identified the presence of such disturbances in cancer survivors more than 10 years post-treatment, which potentially explains the accelerated aging reported in this population [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors

et al. 2018

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BackgroundCancer treatments have substantially improved childhood cancer survival but are accompanied by long-term complications, notably chronic inflammatory diseases. We hypothesize that cancer treatments could lead to long-term epigenetic changes in immune cells, resulting in increased prevalence of inflammatory diseases in cancer survivors.ResultsTo test this hypothesis, we established the epigenetic and transcriptomic profiles of immune cells from 44 childhood cancer survivors (CCS, > 16 years old) on full remission (> 5 years) who had received chemotherapy alone or in combination with total body irradiation (TBI) and hematopoietic stem cell transplant (HSCT). We found that more than 10 years post-treatment, CCS treated with TBI/HSCT showed an altered DNA methylation signature in T cell, particularly at genes controlling immune and inflammatory processes and oxidative stress. DNA methylation remodeling in T cell was partially associated with chronic expression changes of nearby genes, increased frequency of type 1 cytokine-producing T cell, elevated systemic levels of these cytokines, and over-activation of related signaling pathways. Survivors exposed to TBI/HSCT were further characterized by an Epigenetic-Aging-Signature of T cell consistent with accelerated epigenetic aging. To investigate the potential contribution of irradiation to these changes, we established two cell culture models. We identified that radiation partially recapitulated the immune changes observed in survivors through a bystander effect that could be mediated by circulating factors.ConclusionCancer treatments, in particular TBI/HSCT, are associated with long-term immune disturbances. We propose that epigenetic remodeling of immune cells following cancer therapy augments inflammatory- and age-related diseases, including metabolic complications, in childhood cancer survivors.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0561-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors

et al. 2018

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“…Alteration of DNA methylation patterns may depend on altered methyl group transfer during DNA duplication, or on defects of 5mC hydroxylation and demethylation operated by TET enzymes. In cancer and during aging, a substantial fraction of genes undergo a cell type-specific DNA hypermethylation of silenced genomic loci protein that is preceded by H3-K27 and H3-K9 trimethylations [70,71,72,73,74,75,76]. Analogously, an aberrant transcriptional silencing of RASSF1A triggered by the inactivating chromatin modification histone deacetylation and H3-K9 methylation preceded CpG island A hypermethylation [59] (see Klutstein et al [77] for a review).…”

Section: Mechanisms Of Rassf1a Methylation In Cancer and Agingmentioning

confidence: 99%

“…An age-dependent increase of RASSF1A m at differing speeds in different organs of healthy individuals is largely recapitulated in corresponding cancer types [74,75,76,77]. Thus, site-specific DNA hypermethylations that overlap in aging and tumorigenesis candidate these sites as cancer susceptibility hotspots.…”

Section: Mechanisms Of Rassf1a Methylation In Cancer and Agingmentioning

confidence: 99%

Methylation Dynamics of RASSF1A and Its Impact on Cancer

Malpeli

Innamorati

Decimo

et al. 2019

Cancers

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5-methyl cytosine (5mC) is a key epigenetic mark entwined with gene expression and the specification of cellular phenotypes. Its distribution around gene promoters sets a barrier for transcriptional enhancers or inhibitor proteins binding to their target sequences. As a result, an additional level of regulation is added to the signals that organize the access to the chromatin and its structural components. The tumor suppressor gene RASSF1A is a microtubule-associated and multitasking scaffold protein communicating with the RAS pathway, estrogen receptor signaling, and Hippo pathway. RASSF1A action stimulates mitotic arrest, DNA repair and apoptosis, and controls the cell cycle and cell migration. De novo methylation of the RASSF1A promoter has received much attention due to its increased frequency in most cancer types. RASSF1A methylation is preceded by histones modifications and could represent an early molecular event in cell transformation. Accordingly, RASSF1A methylation is proposed as an epigenetic candidate marker in many cancer types, even though an inverse correlation of methylation and expression remains to be fully ascertained. Some findings indicate that the epigenetic abrogation of RASSF1A can promote the alternative expression of the putative oncogenic isoform RASSF1C. Understanding the complexity and significance of RASSF1A methylation is instrumental for a more accurate determination of its biological and clinical role. The review covers the molecular events implicated in RASSF1A methylation and gene silencing and provides a deeper view into the significance of the RASSF1A methylation patterns in a number of gastrointestinal cancer types.

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“…For some patients with solid cancers, epigenetic changes in RASSF1A can be detected in leukocytes [ 4 ], urine [ 5 ], nipple aspirates [ 6 ] and saliva [ 7 ] to support the identification of circulating tumor cells and to highlight non-invasive methods to detect hypermethylation of RASSF1A . Recently, RASSF1A hypermethylation was detected in leukocytes in workers exposed to radiation during the Chernobyl Nuclear Power Plant disaster in Russia in 1986 [ 8 ] to suggest a high susceptibility of the RASSF1A promoter to epigenetic modifications.…”

Section: Introductionmentioning

confidence: 99%

RASSF1A Site-Specific Methylation Hotspots in Cancer and Correlation with RASSF1C and MOAP-1

Volodko

Salla

Zare

et al. 2016

Cancers

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Epigenetic silencing of RASSF1A is frequently observed in numerous cancers and has been previously reported. The promoter region of RASSF1A is predicted to have 75 CpG sites, and very few studies demonstrate how the methylation of these sites affects expression. In addition, the expression relationship between RASSF1A and its downstream target, modulator of apoptosis 1 (MOAP-1), is poorly understood. In this study, we have explored the mRNA expression of RASSF1A, MOAP-1 and the well-characterized splice variant of RASSF1, RASSF1C, in cancer cell lines and primary tumors. We confirmed that the RASSF1A promoter is robustly methylated within a 32-CpG region in solid tumors and results in lower mRNA expression. The MOAP-1 promoter contains ~110 CpG sites, but was not found to be methylated in cancer cell lines when 19 predicted CpG sites were explored. Interestingly, MOAP-1 mRNA expression positively correlated with RASSF1A expression in numerous cancers, whereas RASSF1C expression remained the same or was increased in cell lines or tissues with epigenetic loss of RASSF1A. We speculate that MOAP-1 and RASSF1A may be more intimately connected than originally thought, and the expression of both are warranted in experimental designs exploring the biology of the RASSF1A/MOAP-1 molecular pathway.

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Hypermethylation of gene promoters in peripheral blood leukocytes in humans long term after radiation exposure

Cited by 21 publications

References 54 publications

T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors

T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors

Methylation Dynamics of RASSF1A and Its Impact on Cancer

RASSF1A Site-Specific Methylation Hotspots in Cancer and Correlation with RASSF1C and MOAP-1

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