Age-related DNA hydroxymethylation is enriched for gene expression and immune system processes in human peripheral blood

Johnson, Nicholas; Huang, Luoxiu; Li, Ronghua; Li, Yun; Yang, Yuchen; Kim, Hye Rim; Grant, Crystal D.; Wu, Hao; Whitsel, Eric A.; Kiel, Douglas P.; Baccarelli, Andrea A.; Jin, Peng; Murabito, Joanne M.; Conneely, Karen N.

doi:10.1080/15592294.2019.1666651

Cited by 10 publications

(5 citation statements)

References 66 publications

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“…Age-dependent decreases in DNMT levels and low methyl donor nutrient or high homocysteine levels synergistically aggravate age-dependent DNA methylation changes and subsequently increase aberrant gene expression [ 39 ]. TET enzymes, which are critical for embryonic development via embryonic genome activation [ 40 ], can also be altered by aging [ 41 ]. In an animal study, old mice showed increased hepatic DNA hydroxymethylation compared with that in young mice, whereas no significant difference was observed in hepatic DNA methylation between the young and old mice [ 42 ].…”

Section: Dna Methylation and Agingmentioning

confidence: 99%

Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging

Choi

Friso

2023

Nutr Res Pract

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Healthy aging can be defined as an extended lifespan and health span. Nutrition has been regarded as an important factor in healthy aging, because nutrients, bioactive food components, and diets have demonstrated beneficial effects on aging hallmarks such as oxidative stress, mitochondrial function, apoptosis and autophagy, genomic stability, and immune function. Nutrition also plays a role in epigenetic regulation of gene expression, and DNA methylation is the most extensively investigated epigenetic phenomenon in aging. Interestingly, age-associated DNA methylation can be modulated by one-carbon metabolism or inhibition of DNA methyltransferases. One-carbon metabolism ultimately controls the balance between the universal methyl donor S-adenosylmethionine and the methyltransferase inhibitor S-adenosylhomocysteine. Water-soluble B-vitamins such as folate, vitamin B6, and vitamin B12 serve as coenzymes for multiple steps in one-carbon metabolism, whereas methionine, choline, betaine, and serine act as methyl donors. Thus, these one-carbon nutrients can modify age-associated DNA methylation and subsequently alter the age-associated physiologic and pathologic processes. We cannot elude aging per se but we may at least change age-associated DNA methylation, which could mitigate age-associated diseases and disorders.

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Section: Dna Methylation and Agingmentioning

confidence: 99%

Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging

Choi

Friso

2023

Nutr Res Pract

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“…7H and Table S2) and therefore raised the question of how a methylated Pax5 promoter becomes accessible for Pbx1 binding. Recent studies have shown that hydroxymethylation can alter the chromatin compactness to a state that favors gene expression ( 57 , 58 ). However, bi-sulfite treatment as performed in EPIC sequencing cannot distinguish between methylation and 5′-hydroxymethylation of cytosine (5hmC) ( 59 ).…”

Section: Resultsmentioning

confidence: 99%

Understanding the role of Pax5 in development of taxane-resistant neuroendocrine like prostate cancers

Dutta,

Bhattacharya,

Harris

et al. 2023

Preprint

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Resistance to the current Androgen Receptor Signaling Inhibitor (ARSI) therapies has led to higher incidences of therapy-induced neuroendocrine-like prostate cancer (t-NEPC). This highly aggressive subtype with predominant small cell-like characteristics is resistant to taxane chemotherapies and has a dismal overall survival. t-NEPCs are mostly treated with platinum-based drugs with a combination of etoposide or taxane and have less selectivity and high systemic toxicity, which often limit their clinical potential. During t-NEPC transformation, adenocarcinomas lose their luminal features and adopt neuro-basal characteristics. Whether the adaptive neuronal characteristics of t-NEPC are responsible for such taxane resistance remains unknown. Pathway analysis from patient gene-expression databases indicates that t-NEPC upregulates various neuronal pathways associated with enhanced cellular networks. To identify transcription factor(s) (TF) that could be important for promoting the gene expression for neuronal characters in t-NEPC, we performed ATAC-Seq, acetylated-histone ChIP-seq, and RNA-seq in our NE-like cell line models and analyzed the promoters of transcriptionally active and significantly enriched neuroendocrine-like (NE-like) cancer-specific genes. Our results indicate that Pax5 could be an important transcription factor for neuronal gene expression and specific to t-NEPC. Pathway analysis revealed that Pax5 expression is involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Further results suggest that depletion of Pax5 disrupts cellular interaction in NE-like cells and reduces surface growth factor receptor activation, thereby, sensitizing them to taxane therapies. Moreover, t-NEPC specific hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression. Based on our study, we concluded that continuous exposure to ARSI therapies leads to epigenetic modifications and Pax5 activation in t-NEPC, which promotes the expression of genes necessary to adopt taxane-resistant NE-like cancer. Thus, targeting the Pax5 axis can be beneficial for reverting their taxane sensitivity.

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“…Numerous recent studies have highlighted the critical role for DNA hydroxymethylation in the context of environmental exposures and disease. − DNA hydroxymethylation entails the oxidative conversion of 5-methylcytosine to 5-hydroxymethylcytosine by TET dioxygenases. , While 5-hydroxymethylcytosine is an intermediate in the process of active DNA demethylation, it is also now considered to be a stable epigenetic modification and is associated with regulation of gene expression and alternative splicing. − TET dioxygenases convert 5-methylcytosine to 5-hydroxymethylcytosine using iron (Fe II), α-ketoglutarate, and vitamin C as cofactors, and can also catalyze the further oxidation of 5-hydroxymethylcytosine to 5-formylcytosine and 5-carboxylcytosine. , Like 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine are intermediates in the process of demethylation of DNA through both replication-dependent dilution as well as pathways involving DNA repair enzymes such as thymine DNA glycosylase. , Three TET dioxygenases, TET1, TET2, and TET3 have been identified and each show distinct expression patterns during normal development and in differentiated tissues. , TETs are most highly expressed in embryonic stem cells and during early development, where they function in active DNA demethylation during both waves of reprogramming. 5-Hydroxymethylcytosine is present to a notable degree in embryonic stem cells and the brain. − The specific role of 5-hydroxymethylcytosine in the brain is only beginning to be characterized, but there is evidence to suggest it plays a role in neurodevelopment and aging, and its aberrant expression is implicated in several neurological disorders. , Furthermore, 5-hydroxymethylcytosine is influenced by the environment, with exposures such as arsenic, lead, and pesticides associated with alterations in 5-hydroxymethylcytosine in the brain and blood. ,, Future studies will undoubtedly continue to clarify the role for 5-hydroxymethylcytosine in normal neurodevelopment, environmental health, and disease.…”

Section: Background: Types Of Epigenetic Informationmentioning

confidence: 99%

Toxicoepigenetics and Environmental Health: Challenges and Opportunities

Svoboda

Perera

Morgan

et al. 2022

Chem. Res. Toxicol.

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The rapidly growing field of toxicoepigenetics seeks to understand how toxicant exposures interact with the epigenome to influence disease risk. Toxicoepigenetics is a promising field of environmental health research, as integrating epigenetics into the field of toxicology will enable a more thorough evaluation of toxicant-induced disease mechanisms as well as the elucidation of the role of the epigenome as a biomarker of exposure and disease and possible mediator of exposure effects. Likewise, toxicoepigenetics will enhance our knowledge of how environmental exposures, lifestyle factors, and diet interact to influence health. Ultimately, an understanding of how the environment impacts the epigenome to cause disease may inform risk assessment, permit noninvasive biomonitoring, and provide potential opportunities for therapeutic intervention. However, the translation of research from this exciting field into benefits for human and animal health presents several challenges and opportunities. Here, we describe four significant areas in which we see opportunity to transform the field and improve human health by reducing the disease burden caused by environmental exposures. These include (1) research into the mechanistic role for epigenetic change in environment-induced disease, (2) understanding key factors influencing vulnerability to the adverse effects of environmental exposures, (3) identifying appropriate biomarkers of environmental exposures and their associated diseases, and (4) determining whether the adverse effects of environment on the epigenome and human health are reversible through pharmacologic, dietary, or behavioral interventions. We then highlight several initiatives currently underway to address these challenges.

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Age-related DNA hydroxymethylation is enriched for gene expression and immune system processes in human peripheral blood

Cited by 10 publications

References 66 publications

Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging

Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging

Understanding the role of Pax5 in development of taxane-resistant neuroendocrine like prostate cancers

Toxicoepigenetics and Environmental Health: Challenges and Opportunities

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