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Browsing by Subject "5-hydroxymethylcytosine"
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Item 5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer’s disease(Cell Press, 2021-04-27) Kuehner, Janise N.; Chen, Junyu; Bruggeman, Emily C.; Wang, Feng; Li, Yangping; Xu, Chongchong; McEachin, Zachary T.; Li, Ziyi; Chen, Li; Hales, Chadwick M.; Wen, Zhexing; Yang, Jingjing; Yao, Bing; Medicine, School of Medicine5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer's disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids.Item Ten-eleven translocation protein 1 modulates medulloblastoma progression(BMC, 2021-04-29) Kim, Hyerim; Kang, Yunhee; Li, Yujing; Chen, Li; Lin, Li; Johnson, Nicholas D.; Zhu, Dan; Robinson, M. Hope; McSwain, Leon; Barwick, Benjamin G.; Yuan, Xianrui; Liao, Xinbin; Zhao, Jie; Zhang, Zhiping; Shu, Qiang; Chen, Jianjun; Allen, Emily G.; Kenney, Anna M.; Castellino, Robert C.; Van Meir, Erwin G.; Conneely, Karen N.; Vertino, Paula M.; Jin, Peng; Li, Jian; Biostatistics, School of Public HealthBackground: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes. Results: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes. Conclusions: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.Item Vitamin C regulates Schwann cell myelination by promoting DNA demethylation of pro-myelinating genes(Wiley, 2021-06) Huff, Tyler C.; Sant, David W.; Camarena, Vladimir; Van Booven, Derek; Andrade, Nadja S.; Mustafi, Sushmita; Monje, Paula V.; Wang, Gaofeng; Neurological Surgery, School of MedicineAscorbic acid (vitamin C) is critical for Schwann cells to myelinate peripheral nerve axons during development and remyelination after injury. However, its exact mechanism remains elusive. Vitamin C is a dietary nutrient that was recently discovered to promote active DNA demethylation. Schwann cell myelination is characterized by global DNA demethylation in vivo and may therefore be regulated by vitamin C. We found that vitamin C induces a massive transcriptomic shift (n = 3,848 genes) in primary cultured Schwann cells while simultaneously producing a global increase in genomic 5-hydroxymethylcytosine (5hmC), a DNA demethylation intermediate which regulates transcription. Vitamin C up-regulates 10 pro-myelinating genes which exhibit elevated 5hmC content in both the promoter and gene body regions of these loci following treatment. Using a mouse model of human vitamin C metabolism, we found that maternal dietary vitamin C deficiency causes peripheral nerve hypomyelination throughout early development in resulting offspring. Additionally, dietary vitamin C intake regulates the expression of myelin-related proteins such as periaxin (PRX) and myelin basic protein (MBP) during development and remyelination after injury in mice. Taken together, these results suggest that vitamin C cooperatively promotes myelination through 1) increased DNA demethylation and transcription of pro-myelinating genes, and 2) its known role in stabilizing collagen helices to form the basal lamina that is necessary for myelination.