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Translating epigenetics into clinic: focus on lupus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic relapsing-remitting autoimmune disease with highly heterogeneous phenotypes. Biomarkers with high sensitivity and specificity are useful for early diagnosis as well as monitoring disease activity and long-term complications. Epigenetics potentially provide novel biomarkers in autoimmune diseases. These may include DNA methylation changes in relevant lupus-prone genes or histone modifications and microRNAs to upregulate and downregulate relevant gene expression. The timing and nature of epigenetic modification provide such changes. In lupus, DNA methylation alterations in cytokine genes, such as IFN-related gene and retrovirus gene, have been found to offer biomarkers for lupus diagnosis. Histone modifications such as histone methylation and acetylation lead to transcriptional alterations of several genes such as PTPN22, LRP1B, and TNFSF70. There are varieties of microRNAs applied as lupus biomarkers, including DNMT1-related microRNAs, renal function-associated microRNAs, microRNAs involved in the immune system, and microRNAs for phenotype classification. Thus, we conclude a wide range of promising roles of epigenetic biomarkers aiding in the diagnosing and monitoring of lupus diseases and the risk of organ damage.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5541721 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:Convincing evidence accumulated over the last decades demonstrates the crucial role of epigenetic modifications for mammalian genome regulation and its flexibility. DNA methylation and demethylation is a key mechanism of genome programming and reprogramming. During ontogenesis, the DNA methylome undergoes both programmed changes and those induced by environmental and endogenous factors. The former enable accurate activation of developmental programs; the latter drive epigenetic responses to factors that directly or indirectly affect epigenetic biochemistry leading to alterations in genome regulation and mediating organism response to environmental transformations. Adverse environmental exposure can induce aberrant DNA methylation changes conducive to genetic dysfunction and, eventually, various pathologies. In recent years, evidence was derived that apart from 5-methylcytosine, the DNA methylation/demethylation cycle includes three other oxidative derivatives of cytosine-5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. 5hmC is a predominantly stable form and serves as both an intermediate product of active DNA demethylation and an essential hallmark of epigenetic gene regulation. This makes 5hmC a potential contributor to epigenetically mediated responses to environmental factors. In this state-of-the-art review, we consolidate the latest findings on environmentally induced adverse effects on 5hmC patterns in mammalian genomes. Types of environmental exposure under consideration include hypnotic drugs and medicines (i.e., phenobarbital, diethylstilbestrol, cocaine, methamphetamine, ethanol, dimethyl sulfoxide), as well as anthropogenic pollutants (i.e., heavy metals, particulate air pollution, bisphenol A, hydroquinone, and pentachlorophenol metabolites). We put a special focus on the discussion of molecular mechanisms underlying environmentally induced alterations in DNA hydroxymethylation patterns and their impact on genetic dysfunction. We conclude that DNA hydroxymethylation is a sensitive biosensor for many harmful environmental factors each of which specifically targets 5hmC in different organs, cell types, and DNA sequences and induces its changes through a specific metabolic pathway. The associated transcriptional changes suggest that environmentally induced 5hmC alterations play a role in epigenetically mediated genome flexibility. We believe that knowledge accumulated in this review together with further studies will provide a solid basis for new approaches to epigenetic therapy and chemoprevention of environmentally induced epigenetic toxicity involving 5hmC patterns.

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Translating epigenetics into clinic: focus on lupus.

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