Browsing by Author "Jin, Peng"

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    Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice.
    (Elsevier, 2015-11-24) Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M.; Pan, Feng; Weeks, Ophelia; Zhou, Yuan; Cao, Zeng; Shi, Hui; Wang, Jiapeng; Lin, Li; Chen, Shi; Yuan, Weiping; Qin, Zhaohui; Ni, Hongyu; Nimer, Stephen D.; Yang, Feng-Chun; Jaenisch, Rudolf; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, IU School of Medicine
    TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies.
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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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    Morphological filters in floodplain for DEM-extracted data – using Minimum Bounding Circle & Youden Index
    (2017-06) Jin, Peng; Johnson, Daniel
    Floods are one of the worst disasters in the United States. Each year, the government allocates a tremendous amount of manpower and money on flood prevention initiatives. As the first defense line, levees provide protection from temporary flooding (Makhdoom, 2013). These embankments are broadly classified according to the areas they protect, which could either be urban or agricultural levees within floodplains. In the U.S., most of the levees are handled by government agencies such as the U.S. Army Corps of Engineers and the Federal Emergency Management Services. On the other hand, non-levee embankments created by individual farmers (Olson & Morton, 2013) or naturally formed levee-like structures may not be in the government database. The initial purpose of this research was to assist Polis center on the “Mapping of Non-Levee Embankments in the Indiana” project. The non-levee embankments are not certified or engineered levee-like structures. They, therefore, impose lateral constraints on flood flows, reducing the floodplain storage capacity and increasing the flood velocity. These non-levee embankments can cause stream erosion and downstream flooding. Therefore, it is important to know the locations of these features. The first part of the proposed method adapted the Empirical Bayesian theorem and the low pass filter techniques to extract elevated linear features from LiDAR elevation data – Digital Elevation Model (DEM). The second part of the proposed methods combined the Minimum Bounding Circle (MBC) method and the Youden Index to locate the optimal threshold value that can be used to determine whether the extracted features are levee-like structures. The focus of this study is not only limited to artificial levee-like structures, but also takes the natural levees, or any potential levee-like structures into account because this study assumes all embankments play important roles during flood events.
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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.
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    Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells
    (SpringerNature, 2017-04-25) Pan, Feng; Wingo, Thomas S.; Zhao, Zhigang; Gao, Rui; Makishima, Hideki; Qu, Guangbo; lin, Li; Yu, Miao; Ortega, Janice R.; Wang, Jiapeng; Nazha, Aziz; Chen, Li; Yao, Bing; Liu, Can; Chen, Shi; Weeks, Ophelia; Ni, Hongyu; Phillips, Brittany Lynn; Huang, Suming; Wang, Jianlong; He, Chuan; Li, Guo-Min; Radivoyevitch, Tomas; Aifantis, Iannis; Maciejewski, Jaroslaw P.; Yang, Feng-Chun; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, School of Medicine
    TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2-/- tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2-/- Lin-c-Kit+ cells shows higher mutation frequencies in Tet2-/- cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis.