Browsing by Author "Allen, Emily G."

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    Ethnicity-specific and overlapping alterations of brain hydroxymethylome in Alzheimer’s disease
    (Oxford University Press, 2020-01) Qin, Lixia; Xu, Qian; Li, Ziyi; Chen, Li; Li, Yujing; Yang, Nannan; Liu, Zhenhua; Guo, Jifeng; Shen, Lu; Allen, Emily G.; Chen, Chao; Ma, Chao; Wu, Hao; Zhu, Xiongwei; Jin, Peng; Tang, Beisha; Medicine, School of Medicine
    5-Methylcytosine (5mC), generated through the covalent addition of a methyl group to the fifth carbon of cytosine, is the most prevalent DNA modification in humans and functions as a critical player in the regulation of tissue and cell-specific gene expression. 5mC can be oxidized to 5-hydroxymethylcytosine (5hmC) by ten–eleven translocation (TET) enzymes, which is enriched in brain. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and several studies using the samples collected from Caucasian cohorts have found that epigenetics, particularly cytosine methylation, could play a role in the etiological process of AD. However, little research has been conducted using the samples of other ethnic groups. Here we generated genome-wide profiles of both 5mC and 5hmC in human frontal cortex tissues from late-onset Chinese AD patients and cognitively normal controls. We identified both Chinese-specific and overlapping differentially hydroxymethylated regions (DhMRs) with Caucasian cohorts. Pathway analyses revealed specific pathways enriched among Chinese-specific DhMRs, as well as the shared DhMRs with Caucasian cohorts. Furthermore, two important transcription factor-binding motifs, hypoxia-inducible factor 2α (HIF2α) and hypoxia-inducible factor 1α (HIF1α), were enriched in the DhMRs. Our analyses provide the first genome-wide profiling of DNA hydroxymethylation of the frontal cortex of AD patients from China, emphasizing an important role of 5hmC in AD pathogenesis and highlighting both ethnicity-specific and overlapping changes of brain hydroxymethylome in AD.
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    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 Health
    Background: 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.