Epigenome-wide effects of vitamin D and their impact on the transcriptome of human monocytes involve CTCF

Seuter, Sabine; Neme, Antonio; Carlberg, Carsten

doi:10.1093/nar/gkv1519

“…human monocyte cell culture model [18]. As expected, the vitamin D 3 dose increased the vitamin D status of the study participants, as measured by 25(OH)D 3 serum levels, within one day by some 20%.…”

Section: Discussionsupporting

confidence: 76%

“…The first effect of activating VDR by its ligand is a transient opening or closing of chromatin at specific enhancer and transcription start site (TSS) regions that results in a second step in the activation or repression of vitamin D target genes, such as cathelicidin antimicrobial peptide (CAMP) or PTH, respectively [15]. In THP-1 human monocytic leukemia cells we have demonstrated that the method formaldehyde-assisted isolation of regulatory elements (FAIRE) [16] is well suited to monitor vitamin D-modulated changes in chromatin accessibility [17,18]. This means that vitamin D stimulation of cultured cells, and probably also of human tissues and cell types in vivo, results in changes of the epigenome.…”

Section: Introductionmentioning

confidence: 99%

Molecular evaluation of vitamin D responsiveness of healthy young adults

Seuter

¹

,

Virtanen

²

,

Nurmi

³

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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“…To date, epigenetic effects by vitamin D have primarily been associated with histone modifications, and it is well known that binding of vitamin D to VDR/RXR induces conformational changes that favor release of corepressors and interaction with coactivators and histone acetyltransferases (21,22). Indeed, a recent study using FAIRE-seq in a monocytic cell line demonstrated that vitamin D affects chromatin accessibility at nearly 9,000 sites in the genome (39). The most pronounced effect was observed early after VDR/RXR engagement, causing opening of the chromatin with CCCTC-binding factor (CTCF) being likely involved in this early reprograming.…”

Section: Discussionmentioning

confidence: 99%

“…The type of VDR/RXR-interacting proteins suggests that vitamin D can induce both gene activation and repression (21). Although early response to vitamin D in a monocytic cell line is characterized by activation of gene expression, late response is characterized by the closing of the affected chromatin and similar proportion of up-and down-regulated genes (39). Equal proportion of up-and down-regulated genes has also been described in primary T cells after 10 d of exposure to a vitamin D analog (51).…”

Section: Discussionmentioning

confidence: 99%

“…Patterns of VDR binding (20,35) and gene expression (39,51) in cell lines and healthy subjects have suggested an effect of vitamin D on metabolic and signaling pathways crucial for cell survival, growth, and proliferation. Our data confirm that these pathways are also affected in vivo in CD4+ T cells, mediating the protective effect of the vitamin D supplementation in experimental autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Zeitelhofer

¹

,

Adzemovic

²

,

Gomez-Cabrero

³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS. Vitamin D deficiency is one of the most consistently reported environmental factor in the etiology of multiple sclerosis (MS) (5), a chronic inflammatory disease of the CNS characterized by autoimmune destruction of myelin, axonal loss, and brain atrophy (6). Increased risk of developing MS has been described in carriers of rare and common variants of the CYP27B gene (7, 8), which encodes the enzyme that catalyzes the last step in converting vitamin D to its active form, from 25(OH)D 3 to 1,25 (OH) 2 D 3 . These studies imply a causal role of low vitamin D in MS, which has recently been further supported by Mendelian randomization studies in two large cohorts demonstrating that three genetic variants that associate with serum 25(OH)D 3 levels also associate with the risk of developing MS (9). However, high levels of vitamin D have been associated not only with the reduced risk of developing MS (10, 11) but also with the reduced risk for relapses, new brain lesions, and subsequent disability (12, 13). Moreover, it has been described that increased levels of vitamin D can reduce serum levels of . Most of what is known about the immunological mechanisms of vitamin D in MS comes from the studies in its animal model, experimental autoimmune encephalomyelitis (...

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Vitamin D

Carlberg

¹

2018

Encyclopedia of Life Sciences

0

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The fat‐soluble secosteroid vitamin D 3 is synthesised in UV (ultraviolet)‐B exposed human skin. It regulates calcium and phosphorus homeostasis and thus plays an important role in bone mineralisation. Moreover, vitamin D 3 contributes to the control of cellular growth and differentiation as well as to the responsiveness of the innate and adaptive immune system. At insufficient sun exposure, the molecule is a true vitamin and needs to be taken up via diet or by direct supplementation with pills. During the past 50 000 years, the need of sufficient vitamin D 3 synthesis acted an evolutionary driver for skin lightening of anatomically modern humans migrating out of Africa. The vitamin D 3 metabolite 1α,25‐dihydroxyvitamin D 3 is the exclusive high‐affinity ligand of the transcription factor vitamin D receptor and has a direct effect on the expression of >1000 genes. Thus, vitamin D 3 is a modulator of the human epigenome and transcriptome in more than half of all human tissues and cell types. Key Concepts In UV‐B exposed human skin, the cholesterol precursor 7‐dehydrocholesterol converts to pre‐vitamin D 3 and then isomerises in a nonenzymatic reaction into vitamin D 3 . Lifestyle changes significantly reduced the average endogenous vitamin D 3 production in human and caused vitamin D deficiency in most human populations. Vitamin D 3 is a biologically inert molecule and is enzymatically converted in a two‐step reaction to the nuclear hormone 1,25(OH) 2 D 3 . 25(OH)D 3 serum levels are used as biomarker for the vitamin D status. Only vertebrates have a full vitamin D endocrine system, formed by plasma transport proteins, metabolising enzymes and a high‐affinity receptor. The migration of modern humans to less sunny regions in Asia and Europe caused an evolutionary pressure for genetic adaptation in form of gradual skin lightening for more efficient vitamin D 3 production. The genome‐wide VDR binding pattern is rather cell‐specific, which has an impact on the panel of vitamin D target genes in VDR expressing tissues and cell types. Vitamin D 3 has a direct effect on the accessibility of chromatin, that is it serves as a modulator of the epigenome. Humans have an individual response to vitamin D 3 , referred to a vitamin D response index, which allows segregation into high, mid and low responders. The vitamin D response index suggests for each individual a vitamin D 3 supplementation protocol that will direct to a personal optimal vitamin D status.

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Epigenome-wide effects of vitamin D and their impact on the transcriptome of human monocytes involve CTCF

Cited by 102 publications

References 57 publications

Molecular evaluation of vitamin D responsiveness of healthy young adults

Molecular evaluation of vitamin D responsiveness of healthy young adults

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

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