Alternative splicing of the vitamin D receptor modulates target gene expression and promotes ligand-independent functions

Annalora, Andrew J.; Jozic, Marija; Marcus, Carol S.; Iversen, Patrick L.

doi:10.1016/j.taap.2018.12.009

Cited by 10 publications

(18 citation statements)

References 104 publications

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“…For example, both vitamin D and IL-33 promote the differentiation of Th2 lymphocytes by inhibiting Th1 differentiation and also act as inducers of immunoregulatory cells. Vitamin D can downregulate the production of inflammatory cytokines and chemokines (121). Moreover, vitamin D activity is determined through vitamin D receptors, which are present not only in the skeleton but also in different types of cells, including antigenpresenting-cells, immune cells, and keratinocytes.…”

Section: Vitamin D and Il-33 Immunological Crosstalkmentioning

confidence: 99%

“…IL-33 may act as an alarmin, exerting both repairing and damaging processes and functioning as a nuclear transcription factor. Similarly, the vitamin D receptor, functioning as a ligand-activated transcription factor, regulates the activation or repression of gene transcription (121). Moreover, vitamin D deficiency likely independently contributes to the increased incidence of OP in Pso patients.…”

Section: Vitamin D and Il-33 Immunological Crosstalkmentioning

confidence: 99%

“…The frequent of onset of OP during Pso could also be conditioned by the effective variability of effects of IL-33 on bone remodeling, which are dependent on a wide range of other factors (inflammatory microenvironment, influence of other cytokines, hormones, and vitamins) (9). A vitamin D deficiency could somehow nullify the protective effect of IL-33 on bone through mechanisms that are still unclear (121). Figure 1 summarizes the complex interaction between vitamin D deficiency and increased IL-33/ST2 axis expression leading to increased bone resorption and OP in Pso.…”

Section: The Paradox Of the Vitamin D And Il-33 Relationship In Pso-amentioning

confidence: 99%

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IL-33/Vitamin D Crosstalk in Psoriasis-Associated Osteoporosis

et al. 2021

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Patients with psoriasis (Pso) and, in particular, psoriatic arthritis (PsoA) have an increased risk of developing osteoporosis (OP). It has been shown that OP is among the more common pathologies associated with Pso, mainly due to the well-known osteopenizing conditions coexisting in these patients. Pso and OP share common risk factors, such as vitamin D deficiency and chronic inflammation. Interestingly, the interleukin (IL)-33/ST2 axis, together with vitamin D, is closely related to both Pso and OP. Vitamin D and the IL-33/ST2 signaling pathways are closely involved in bone remodeling, as well as in skin barrier pathophysiology. The production of anti-osteoclastogenic cytokines, e.g., IL-4 and IL-10, is promoted by IL-33 and vitamin D, which are stimulators of both regulatory and Th2 cells. IL-33, together with other Th2 cytokines, shifts osteoclast precursor differentiation towards macrophage and dendritic cells and inhibits receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis by regulating the expression of anti-osteoclastic genes. However, while the vitamin D protective functions in OP and Pso have been definitively ascertained, the overall effect of IL-33 on bone and skin homeostasis, because of its pleiotropic action, is still controversial. Emerging evidence suggests a functional link between vitamin D and the IL-33/ST2 axis, which acts through hormonal influences and immune-mediated effects, as well as cellular and metabolic functions. Based on the actions of vitamin D and IL-33 in Pso and OP, here, we hypothesize the role of their crosstalk in the pathogenesis of both these pathologies.

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Section: Vitamin D and Il-33 Immunological Crosstalkmentioning

confidence: 99%

Section: Vitamin D and Il-33 Immunological Crosstalkmentioning

confidence: 99%

Section: The Paradox Of the Vitamin D And Il-33 Relationship In Pso-amentioning

confidence: 99%

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IL-33/Vitamin D Crosstalk in Psoriasis-Associated Osteoporosis

et al. 2021

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“…To mention some recent findings concerning CRC, it was shown that alterations in alternative splicing are involved in tumour cell proliferation [ 11 , 12 , 13 , 14 , 15 , 16 ] and invasiveness [ 15 , 17 , 18 , 19 , 20 , 21 , 22 ]. Consequently, the analysis of splice variants has been proposed as a tool for the diagnosis or prognosis of CRC [ 14 , 23 , 24 , 25 , 26 ] and the possibility of targeting specific variants or splicing modulators for therapeutic purposes has also been postulated [ 22 , 26 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer

Gimeno-Valiente

Riffo‐Campos

Torres

et al. 2021

Cancers

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The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing ZNF518B on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing ZNF518B are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is ZNF518B-dependent in KAT2B, RGS4 and EFNA5; the level of H3K27me3 changes in accordance. G9A also binds RGS4 and PADI3 in a ZNF518B-dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.

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“…SSO technology has primarily been exploited as a therapeutic approach to rare genetic diseases such as Duchenne muscular dystrophy (Fall et al, 2006;McClorey et al, 2006a,b;Adams et al, 2007;Fletcher et al, 2007;Koo and Wood, 2013) as highlighted by the Food and Drug Administration approval of Eteplirsen in 2016 (Syed, 2016). The therapeutic utility of SSOs to modulate the immune response have also been explored (Mourich and Iversen, 2009;Mourich et al, 2014;Panchal et al, 2014), as has ligand-independent signaling in the vitamin D receptor (Annalora et al, 2019). The implications of splice-switching small molecules and SSOs as gene-directed therapeutics targeting the pre-mRNA of NR genes underlie the examination of NR splice variants presented here.…”

Section: Introductionmentioning

confidence: 99%

Alternative Splicing in the Nuclear Receptor Superfamily Expands Gene Function to Refine Endo-Xenobiotic Metabolism

Annalora

Marcus

Iversen

2020

Drug Metabolism and Disposition

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The human genome encodes 48 nuclear receptor (NR) genes, whose translated products transform chemical signals from endoxenobiotics into pleotropic RNA transcriptional profiles that refine drug metabolism. This review describes the remarkable diversification of the 48 human NR genes, which are potentially processed into over 1000 distinct mRNA transcripts by alternative splicing (AS). The average human NR expresses ∼21 transcripts per gene and is associated with ∼7000 single nucleotide polymorphisms (SNPs). However, the rate of SNP accumulation does not appear to drive the AS process, highlighting the resilience of NR genes to mutation. Here we summarize the altered tissue distribution/function of well characterized NR splice variants associated with human disease. We also describe a cassette exon visualization pictograph methodology for illustrating the location of modular, cassette exons in genes, which can be skipped in-frame, to facilitate the study of their functional relevance to both drug metabolism and NR evolution. We find cassette exons associated with all of the functional domains of NR genes including the DNA and ligand binding domains. The matrix of inclusion or exclusion for functional domain-encoding cassette exons is extensive and capable of significant alterations in cellular phenotypes that modulate endo-xenobiotic metabolism.Exon inclusion options are differentially distributed across NR subfamilies, suggesting group-specific conservation of resilient functionalities. A deeper understanding of this transcriptional plasticity expands our understanding of how chemical signals are refined and mediated by NR genes. This expanded view of the NR transcriptome informs new models of chemical toxicity, disease diagnostics, and precision-based approaches to personalized medicine. SIGNIFICANCE STATEMENTThis review explores the impact of alternative splicing (AS) on the human nuclear receptor (NR) superfamily and highlights the dramatic expansion of more than 1000 potential transcript variants from 48 individual genes. Xenobiotics are increasingly recognized for their ability to perturb gene splicing events, and here we explore the differential sensitivity of NR genes to AS and chemical exposure. Using the cassette exon visualization pictograph methodology, we have documented the conservation of splice-sensitive, modular, cassette exon domains among the 48 human NR genes, and we discuss how their differential expression profiles may augment cellular resilience to oxidative stress and fine-tune adaptive, metabolic responses to endo-xenobiotic exposure.

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Alternative splicing of the vitamin D receptor modulates target gene expression and promotes ligand-independent functions

Cited by 10 publications

References 104 publications

IL-33/Vitamin D Crosstalk in Psoriasis-Associated Osteoporosis

IL-33/Vitamin D Crosstalk in Psoriasis-Associated Osteoporosis

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer

Alternative Splicing in the Nuclear Receptor Superfamily Expands Gene Function to Refine Endo-Xenobiotic Metabolism

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