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1. The Epigenetic Landscape 

1. The Epigenetic Landscape 

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Here, we present the first volume of a multi-volume series on Retinoic Acid Signaling that will cover all aspects of this broad and diverse field. One aim of Volume I is to present a compilation of topics related to the biochemistry of nuclear retinoic acid receptors, from their architecture when bound to DNA and associated with their coregulators...

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... We did not identify any variation in the expression of the main components of the canonical carotenoid metabolism pathway; however, two genes related to carotenoid metabolism were found in the 36 genes signature (RARRES1 and ALDH1A3). Indeed, an analysis based on the seven most relevant genes related to carotenoid metabolism failed to match the spectral morphology of the two Raman groups, meaning that post-translational regulation might occur, as it has been already been showed for the main Vitamin A receptors.18,19 Amongst the 36 most significant genes linked to spectral characteristics, we identified two minimal sets of genes with different interests: one F I G U R E 4 Raman signature and survival prediction. ...
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Raman spectroscopy is an imaging technique that has been applied to assess molecular compositions of living cells to characterize cell types and states. However, owing to the diverse molecular species in cells and challenges of assigning peaks to specific molecules, it has not been clear how to interpret cellular Raman spectra. Here, we provide firm evidence that cellular Raman spectra (RS) and transcriptomic profiles of glioblastoma can be computationally connected and thus interpreted. We find that the dimensions of high-dimensional RS and transcriptomes can be reduced and connected linearly through a shared low-dimensional subspace. Accordingly, we were able to predict global gene expression profiles by applying the calculated transformation matrix to Raman spectra and vice versa. From these analyses, we extract a minimal gene expression signature associated with specific RS profiles and predictive of disease outcome.
... This term was devised by C. H. Waddington in 1942, but only gained popularity in the 1990s [15]. Waddington defined the term 'epigenetics' as "the branch of biology which studies the casual interactions between genes and their products, which bring the phenotype into being" [16,17]. It was an early definition that we now mostly associate with organismal development. ...
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The credibility of the Weismann barrier has come into question. Several studies in various animal systems, from mice to worms, have shown that novel environmental stimuli can generate an altered developmental or behavioral trait that can be transmitted to offspring of the following generation. Recently, insects have become ideal models to study the inheritance of acquired traits. This is because insects can be reared in high numbers at low cost, they have short generation times and produce abundant offspring. Numerous studies have shown that an insect can modify its phenotype in response to a novel stimulus to aid its survival, and also that this modified phenotypic trait can be inherited by its offspring. Epigenetic mechanisms are likely at play but, most studies do not address the mechanisms that underlie the inheritance of acquired traits in insects. Here we first review general epigenetic mechanisms such as DNA methylation, histone acetylation and small noncoding RNAs that have been implicated in the transmission of acquired traits in animals, then we focus on the few insect studies in which these mechanisms have been investigated.
... Several experimental and clinical studies have investigated the effects of ATRA combined with valproic acid in the treatment of AML. Important characteristics of the two drugs are summarized in Table 1 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Additional studies are needed to further characterize the possible mechanisms for interactions between the two drugs at the cellular level, especially whether such interactions differ between patients and depend on karyotype and/or molecular genetic abnormalities. ...
... Table 1. Important characteristics of valproic acid and all-trans retinoic acid (ATRA) [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. ...
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... The availability of retinoic acid (RA), a natural derivative of vitamin A, modifies the histone patterns. RA treatment increases H3K4 and decreases H3K27, and it increases H3K9 and H3K14 acetylation in humans [82]. A diet deficient of vitamin A decreases HAT activity and H3 and H4 histones acetylation in rats [83]. ...
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... In contrast, the upregulation of hepatic RA biosynthesis and signaling in T1D might contribute to metabolic inflexibility associated with this disease. ______________________________________ Numerous studies have demonstrated that the bioactive derivative of vitamin A, retinoic acid (RA), is essential for proper embryonic development [1][2][3], robust immune responses [4][5], male fertility [6,7], epigenetic regulation [8][9][10] and maintenance of circadian rhythms [11][12][13]. Especially well established is the role of RA during embryogenesis [2,3]. ...
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Liver is the central metabolic hub that coordinates carbohydrate and lipid metabolism. The bioactive derivative of vitamin A, retinoic acid (RA) was shown to regulate major metabolic genes including phosphoenolpyruvate carboxykinase, fatty acid synthase, carnitine palmitoyltransferase 1, and glucokinase among others. Expression levels of these genes undergo profound changes during adaptation to fasting, or in metabolic diseases such as type 1 diabetes (T1D). However, it is unknown whether the levels of hepatic RA change during metabolic remodeling. This study investigated the dynamics of hepatic retinoid metabolism and signaling in the fed state, in fasting, and in T1D. Our results show that fed-to-fasted transition is associated with significant decrease in hepatic retinol dehydrogenase (RDH) activity, the rate-limiting step in RA biosynthesis, and downregulation of RA signaling. The decrease in RDH activity correlates with the decreased abundance and altered subcellular distribution of RDH10 while Rdh10 transcript levels remain unchanged. In contrast to fasting, untreated T1D is associated with upregulation of RA signaling and an increase in hepatic RDH activity, which correlates with the increased abundance of RDH10 in microsomal membranes. The dynamic changes in RDH10 protein levels in the absence of changes in its transcript levels imply the existence of post-transcriptional regulation of RDH10 protein. Together, these data suggest that the downregulation of hepatic RA biosynthesis, in part via the decrease in RDH10, is an integral component of adaptation to fasting. In contrast, the upregulation of hepatic RA biosynthesis and signaling in T1D might contribute to metabolic inflexibility associated with this disease.
... 79 Urvalek et al refer to this situation as "push-pull effect". 18 A similar "push-pull" activity is conferred to The Polycomb repressive complex 2 (PRC2) that involves EZH2, an H3K27 methyltransferase, and KDM5B, an H3K4 ...
... This push-pull effect and resolution of bivalent chromatin domains upon RA induction have been shown in several studies. 18 Another aspect, which links RA-signaling with bivalent domains, is the regulation of DNA methylation. It is known that thymine DNA glycosylase (TDG), a base excision repair enzyme, maintains bivalent chromatin domains in embryonic stem cells by facilitating base excision repair with the purpose of antagonizing aberrant DNA methylation. ...
... (p300) to the promoters of RA-target genes. 18,82 Therefore, a defect in TDG function may eventuate with a reduction in RAR/RA-related gene transcription and defects in cell differentiation. 83 In addition to the changes in the levels of bivalent histone marks upon RA stimulation as explained above, H3K27, H3K9 and H3K14 ...
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... Epigenetic changes involving methylation of DNA and/or modification to histones by acetylation, ubiquitination, methylation, phosphorylation, SUMOylation, glycosylation, or biotinylation represent an innate mechanism that links nutritional status to gene expression, and play a critical role in many cellular processes [180][181][182][183][184][185][186]. The enzymes responsible for these modifications include histone acetyltransferases (HATs), histone deacetylases (HDACs), methyltransferases (KMTs), and demethylases (KDMs) [187][188][189]. ...
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The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer.
... Epigenetics refers to a change in chromatin that leads to the regulation of gene expression without alterations in the DNA sequence [6]. Epigenetic modifications include DNA methylation, and/or histone modifications by acetylation, ubiquitination, methylation, phosphorylation, sumoylation, glycosylation, and biotinylation, changes that play a critical role in many cellular processes [7][8][9][10][11][12][13]. The enzymes responsible for these modifications include histone acetyltransferases (HATs), histone deacetylases (HDACs), methyltransferases (KMTs), and demethylases (KDMs) [14][15][16]. ...
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Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial–mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism–epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.
... These genes are further involved in epigenetic regulation in the cells (Fazi et al. 2005). Several studies provide evidence of RA-mediated cancer treatment alone or in combination with various drugs by modifying the epigenetic landscape of the body (Urvalek, Laursen, and Gudas 2014). Another study (Ferrari, Pfeffer, and Vidali 1988) demonstrated in vivo binding of retinol to the nucleosome complex, which further modifies the chromatin structure and regulates its function. ...
... Vitamin A-mediated DNA demethylation is closely associated with various patho-physiological conditions ( Figure 1A). RARs and specifically RARa involved in specific promoter hypomethylation and reduced expression of RARa may trigger leukemogenesis development (Urvalek, Laursen, and Gudas 2014). Involvement of Vitamin A in the embryonic reprograming of stem cells is well studied and is mediated through the ten-eleven translocation (TET) demethylases, which erase DNA methylation marks. ...
... For example, heat map of Hox (homeobox) gene cluster that plays an important role during embryonic development, shows increase in H3K4me3 and H3ac activation mark and decrease in repressive mark H3K27me3 in response to RA treatment. It also increases H3K9 and H3K14 acetylation, which further leads to transcriptional activation (Urvalek, Laursen, and Gudas 2014). Another example of epigenetic change that occurs in response to RA and their relationship to cell differentiation is discussed by Gudas (2013). ...
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Epigenetic modifications play an important role in disease pathogenesis and therefore are a focus of intense investigation. Epigenetic changes include DNA, RNA, and histone modifications along with expression of non-coding RNAs. Various factors such as environment, diet, and lifestyle can influence the epigenome. Dietary nutrients like vitamins can regulate both physiological and pathological processes through their direct impact on epigenome. Vitamin A acts as a major regulator of above-mentioned epigenetic mechanisms. B group vitamins including biotin, niacin, and pantothenic acid also participate in modulation of various epigenome. Further, vitamin C has shown to modulate both DNA methylation and histone modifications while few reports have also supported its role in miRNA-mediated pathways. Similarly, vitamin D also influences various epi-genetic modifications of both DNA and histone by controlling the regulatory mechanisms. Despite the information that vitamins can modulate the epigenome, the detailed mechanisms of vitamin-mediated epigenetic regulations have not been explored fully and hence further detailed studies are required to decipher their role at epigenome level in both normal and disease pathogenesis. The current review summarizes the available literature on the role of vitamins as epigenetic modi-fier and highlights the key evidences for developing vitamins as potential epidrugs.
... Epigenetic modification has been proposed in the treatment of both AD [69] and aging [70]. This may be another mechanism by which RA can influence cognitive decline and aging given the capacity of RA to regulate epigenetic change [71]. ...
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Retinoic acid has been previously proposed in the treatment of Alzheimer’s disease (AD). Here, five transgenic mouse models expressing AD and frontotemporal dementia risk genes (i.e., PLB2APP, PLB2TAU, PLB1Double, PLB1Triple, and PLB4) were used to investigate if consistent alterations exist in multiple elements of the retinoic acid signaling pathway in these models. Many steps of the retinoic acid signaling pathway including binding proteins and metabolic enzymes decline, while the previously reported increase in RBP4 was only consistent at late (6 months) but not early (3 month) ages. The retinoic acid receptors were exceptional in their consistent decline in mRNA and protein with transcript decline of retinoic acid receptors β and γ by 3 months, before significant pathology, suggesting involvement in early stages of disease. Decline in RBP1 transcript may also be an early but not late marker of disease. The decline in the retinoic acid signaling system may therefore be a therapeutic target for AD and frontotemporal dementia. Thus, novel stable retinoic acid receptor modulators (RAR-Ms) activating multiple genomic and non-genomic pathways were probed for therapeutic control of gene expression in rat primary hippocampal and cortical cultures. RAR-Ms promoted the non-amyloidogenic pathway, repressed lipopolysaccharide induced inflammatory genes and induced genes with neurotrophic action. RAR-Ms had diverse effects on gene expression allowing particular RAR-Ms to be selected for maximal therapeutic effect. Overall the results demonstrated the early decline of retinoic acid signaling in AD and frontotemporal dementia models and the activity of stable and potent alternatives to retinoic acid as potential therapeutics.