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The Epigenetic Role of Vitamin C in Neurological Development and Disease
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Vitamin C may also be critical for maintaining histone methylation dynamics. JmjC domain-containing histone lysine demethylases (KDMs) are the largest enzyme family responsible for histone demethylation and are also members of the Fe(II) and 2OG-dependent dioxygenase superfamily [15]. KDMs are grouped into seven subfamilies based on sequence conservation and the methylated lysine residues that they antagonize. Containing nearly 20 members in total, KDMs are able to recognize and alter the methylation states of all histone lysine residues in order to drive downstream effects that are relevant to both health and disease [16]. KDMs are known to be critical for processes involved in development and mammalian disease states: For instance, JARID2 is known to associate with the Polycomb complex in embryonic stem cells (ESCs) and is essential for ESC differentiation, while KDM3A is critical for mouse spermatogenesis and is implicated in both fertility and obesity [17–19]. The importance of KDMs is wide reaching, and the role of vitamin C in sustaining their activity in critical physiologic processes is becoming more apparent. Vitamin C has been demonstrated to optimize the activity of KDM2, induce KDM-mediated somatic reprogramming, trigger embryonic stem cell demethylation, and alter global DNA and histone methylation to ensure oocyte maturation and developmental competence [20–23]. The role of vitamin C in propagating both DNA and histone demethylation may have a potentially widespread impact on numerous developmental processes and disease states, especially those regarding the nervous system, since neuronal cells contain one of the highest concentrations of intracellular vitamin C [24]. Histone and DNA methylation dynamics underlie nearly every neurological function and disease; thus, the epigenetic role of vitamin C in neural development and pathology deserves elucidation and speculation.
Global methylation profiles in buccal cells of long-term smokers and moist snuff consumers
Published in Biomarkers, 2018
Walter J. Jessen, Michael F. Borgerding, G. L. Prasad
In the TR signature, immune response was the most enriched functional category, consisting of seventeen pathways or processes (42 total genes, 45% (19) are hyper- or hypo-methylated). Almost half of the TR immune response signature encodes nuclear proteins (20) while another 26% (11) encode cytoplasmic proteins; eight genes encode membranes and three encode extracellular proteins. The process of T cell differentiation was identified in the TR signature; all four genes were hyper-methylated and predicted to be up-regulated (Table 4). This is consistent with the predicted up-regulation of the CTR genes involved in T cell activation (Table 2). With the exception of one gene – JARID2 – all 18 other signature genes were hyper-methylated. Prominent features of this category and associated candidate biomarkers differentially methylated include response to cytokine stimulus (HDAC4) and response to wounding (HDAC4, NFATC4, PPARD, TGFBR2, TLR1, TNFAIP6, TOLLIP and VWF).
A study of single nucleotide polymorphisms in CD157, AIM2 and JARID2 genes in Han Chinese children with autism spectrum disorder
Published in Nordic Journal of Psychiatry, 2018
Weiming Mo, Jun Liu, Zengyu Zhang, Hong Yu, Aiping Yang, Fei Qu, Pingfang Hu, Zhuo Liu, Fengpei Hu
Activation of AIM2-inflammasomes was attributed to ASD-associated neuroinflammation [20]. In a two-stage genome-wide association study, a total of 166 ASD families (n = 500) and 642 healthy controls in an East Asian population were enrolled in a discovery cohort. Another 205 Japanese ASD cases and 184 healthy controls, as well as 418 Chinese Han trios (n = 1,254) were genotyped as the validation cohort. Among roughly 900,000 genotyped SNPs, rs855867 in AIM2 gene and rs2237126 in JARID2 gene were identified and validated to be associated with ASD [27]. Using the Autism Genetic Resource Exchange (AGRE) repository, family-based tests of association were conducted on the 22,904 single nucleotide polymorphisms (SNPs) from the 2012 immune-related genes on 1510 trios. SNP rs13193457 (JARID2) was one of the SNPs significantly associated with ASD [28]. ASD patients were found to have interstitial deletions of the short arm of chromosome 6, a region harboring the JARID2 gene [35]. Subsequent studies showed that deletion of the region was related to ASD with severe intellectual disability [21,36].
Up-regulated miR-155 is associated with poor prognosis in childhood acute lymphoblastic leukemia and promotes cell proliferation targeting ZNF238
Published in Hematology, 2021
Cong Liang, Yu Li, Li-Na Wang, Xiao-Li Zhang, Jie-Si Luo, Chun-Jin Peng, Wen-Yan Tang, Li-Bin Huang, Yan-Lai Tang, Xue-Qun Luo
Computational prediction of human miRNA targets from StarBase suggested that miR-155 can modulate more than 1000 genes (Figure 4(A)). To further explore the underlying mechanism of miR-155 regulatory network, we performed KEGG analysis of these targets of miR-155. The results proposed that miR-155 might participate in cellular mechanisms associated with ALL dysregulation (eg, PI3K-Akt, mTOR, and AMPK) (Figure 4(B)). To further identify a functional miR-155 target, we chosen the genes that were predicted by at least four databases simultaneously. 75 of the putative miR-155 targets met the requirements. Then, we performed correlation analysis of miRNA and target genes in leukemia (p>0.05). Sixteen of the target non-oncogenes in leukemia were significantly correlated with miR-155 (Table 2). Among them, JARID2, PHF17, RREB1, SDCBP and BACH1 had been already demonstrated as the targets of miR-155 in leukemia. Previous studies have proposed that ZNF238 is the novel tumor suppressor in human brain cancer [24], which can drastically decrease proliferation and promote cell death in medulloblastoma and glioblastoma multiforme cells [25]. However, the role of ZNF238 in childhood ALL is unknown. Figure 4(C) shows the predicted binding sites between miR-155 and ZNF238. Dual luciferase reporter assay was performed in HEK-293 T cells (Figure 4(D)). Furthermore, the expression of ZNF238 was inhibited at the protein and mRNA levels in CEM-C1 and MOLT-4 cells transfected with miR-155 mimics, miR-155 inhibitors, and corresponding controls (Figure 4(E,G)). To analyze ZNF238 expression between childhood ALL patients and healthy controls, we chose Coustan-Smith Leukemia dataset in ONCOMINE database, which contains 46 children with T-ALL, 238 children with B- ALL and 4 healthy controls. We found that ZNF238 was significantly reduced in children ALL (Figure 4(H)).