Jiaqi Sun, Junzheng Yang, Xiaoli Miao, Horace H Loh, Duanqing Pei, Hui Zheng
BACKGROUND: Epigenetic modifications, namely non-coding RNAs, DNA methylation, and histone modifications such as methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation play a significant role in brain development. DNA methyltransferases, methyl-CpG binding proteins, and ten-eleven translocation proteins facilitate the maintenance, interpretation, and removal of DNA methylation, respectively. Different forms of methylation, including 5-methylcytosine, 5-hydroxymethylcytosine, and other oxidized forms, have been detected by recently developed sequencing technologies...
March 2, 2021: Cell Regeneration
Sreejana Ray, Desiree Tillo, Stewart R Durell, Syed Khund-Sayeed, Charles Vinson
NFATc2 is a DNA binding protein in the Rel family transcription factors, which binds a CGGAA motif better when both cytosines in the CG dinucleotide are methylated. Using protein binding microarrays (PBMs), we examined the DNA binding of NFATc2 to three additional types of DNA: single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with either 5-methylcytosine (5mC, M ) or 5-hydroxymethylcytosine (5hmC, H ) in one strand and a cytosine in the second strand. ATTTCCAC , the complement of the core GGAA motif, is better bound as ssDNA compared to dsDNA...
February 16, 2021: ACS Omega
Rebecca Broome, Igor Chernukhin, Stacey Jamieson, Kamal Kishore, Evangelia K Papachristou, Shi-Qing Mao, Carmen Gonzalez Tejedo, Areeb Mahtey, Vasiliki Theodorou, Arnoud J Groen, Clive D'Santos, Shankar Balasubramanian, Anca Madalina Farcas, Rasmus Siersbæk, Jason S Carroll
Estrogen receptor-α (ER) drives tumor development in ER-positive (ER+) breast cancer. The transcription factor GATA3 has been closely linked to ER function, but its precise role in this setting remains unclear. Quantitative proteomics was used to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, few proteins were lost from the ER complex in the absence of GATA3, with the only major change being depletion of the dioxygenase TET2. TET2 binding constituted a near-total subset of ER binding in multiple breast cancer models, with loss of TET2 associated with reduced activation of proliferative pathways...
February 23, 2021: Cell Reports
Xin-Yu Fan, Guang Shi, Xiao-Jing He, Xin-Yang Li, Yu-Xiao Wan, Ling-Yan Jian
Oxycodone is one of the most commonly used analgesics in the clinic. However, long-term use can contribute to drug dependence. Accumulating evidence of changes in DNA methylation after opioid relapse has provided insight into mechanisms underlying drug-associated memory. The neuropeptide oxytocin is reported to be a potential treatment for addiction. The present study sought to identify changes in global and synaptic gene methylation after cue-induced reinstatement of oxycodone conditioned place preference (CPP) and the effect of oxytocin...
February 20, 2021: Addiction Biology
Kanokporn Noy Rithidech, Witawat Jangiam, Montree Tungjai, Paiboon Reungpatthanaphong, Chris Gordon, Louise Honikel
<u>Purpose</u>: To determine the early- and late-occurring damage in the bone marrow (BM) and peripheral blood cells of male CBA/Ca mice after exposure to 0, 0.1, 0.25, or 0.5 Gy of 1 GeV/n titanium (48 Ti) ions (one type of space radiation). <u>Method</u>: We used the mouse in vivo blood-erythrocyte micronucleus (MN) assay for evaluating the cytogenetic effects of various doses of 1 GeV/n 48 Ti ions. The MN assay was coupled with the characterization of epigenetic alterations (the levels of global 5-methylcytosine and 5-hydroxymethylcytosine) in DNA samples isolated from BM cells...
February 16, 2021: International Journal of Radiation Biology
Brian C-H Chiu, Chang Chen, Qiancheng You, Rudyard Chiu, Girish Venkataraman, Chang Zeng, Zhou Zhang, Xiaolong Cui, Sonali M Smith, Chuan He, Wei Zhang
The 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. We identified 294 differentially modified genes between DLBCL and FL. The differential 5hmC in the DLBCL/FL-differentiating genes co-localized with enhancer marks H3K4me1 and H3K27ac...
February 11, 2021: NPJ Genomic Medicine
Hang-Yu Chen, Wei-Long Zhang, Lei Zhang, Ping Yang, Fang Li, Ze-Ruo Yang, Jing Wang, Meng Pang, Yun Hong, Changjian Yan, Wei Li, Jia Liu, Nuo Xu, Long Chen, Xiu-Bing Xiao, Yan Qin, Xiao-Hui He, Hui Liu, Hai-Chuan Zhu, Chuan He, Jian Lin, Hong-Mei Jing
BACKGROUND: Although R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard chemotherapy regimen for diffuse large B cell lymphoma (DLBCL) patients, not all patients are responsive to the scheme, and there is no effective method to predict treatment response. METHODS: We utilized 5hmC-Seal to generate genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) from 86 DLBCL patients before they received R-CHOP chemotherapy...
February 11, 2021: Clinical Epigenetics
Jamie E DeNizio, Blaine J Dow, Juan C Serrano, Uday Ghanty, Alexander C Drohat, Rahul M Kohli
In mammalian genomes, cytosine methylation occurs predominantly at CG (or CpG) dinucleotide contexts. As part of dynamic epigenetic regulation, 5-methylcytosine (mC) can be erased by active DNA demethylation, whereby ten-eleven translocation (TET) enzymes catalyze the stepwise oxidation of mC to 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxycytosine (caC), thymine DNA glycosylase (TDG) excises fC or caC, and base excision repair yields unmodified cytosine. In certain cell types, mC is also enriched at some non-CG (or CH) dinucleotides, however hmC is not...
February 6, 2021: Journal of Molecular Biology
Masako Tada, Ayaka Hayashi, Yumi Asano, Musashi Kubiura-Ichimaru, Takamasa Ito, Miho Yoshii, Hiroshi Kimura, Yoichi Matsuda, Mitsuo Oshimura
BACKGROUND: DNA methylation is a significant epigenetic modification that is evolutionarily conserved in various species and often serves as a repressive mark for transcription. DNA methylation levels and patterns are regulated by a balance of opposing enzyme functions, DNA methyltransferases, DNMT1/3A/3B and methylcytosine dioxygenases, TET1/2/3. In mice, the TET enzyme converts DNA cytosine methylation (5mC) to 5-hydroxymethylcytosine (5hmC) at the beginning of fertilisation and gastrulation and initiates a global loss of 5mC, while the 5mC level is increased on the onset of cell differentiation during early embryonic development...
February 8, 2021: Genes & Genomics
Dong Hyun Kang, Dong Jun Jeong, Tae Sung Ahn, Hyun Yong Lee, Han Jo Kim, Sang Byung Bae, Hyeong Joo Kim, Moon Soo Lee, Hyog Young Kwon, Moo-Jun Baek
Inactivation of the ten-eleven translocation (TET) family members and catalyzation of 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) is associated with cancer initiation and progression. AMP-activated protein kinase (AMPK) is an enzyme that stabilizes TET2; however, the clinical relevance of AMPK and TET2 expression levels is currently unclear. Therefore, the present study aimed to investigate the clinical implications of AMPK/TET2 expression levels in colorectal cancer (CRC). Immunohistochemistry was used to retrospectively examine the expression levels of AMPK and TET2 in paraffin-embedded specimens obtained from 343 patients with CRC...
February 2021: Oncology Letters
T Sharapova, N Talaty, W R Buck, S Fossey, M J Liguori, T R Van Vleet
Non-genotoxic carcinogens (NGCs) are known to cause perturbations in DNA methylation, which can be an early event leading to changes in gene expression and the onset of carcinogenicity. Phenobarbital (PB) has been shown to alter liver DNA methylation and hydroxymethylation patterns in mice in a time dependent manner. The goals of this study were to assess if clofibrate (CFB), a well-studied rodent NGC, would produce epigenetic changes in mice similar to PB, and if a methyl donor supplementation (MDS) would modulate epigenetic and gene expression changes induced by phenobarbital...
February 4, 2021: Toxicology and Applied Pharmacology
Guang Song, Guohua Wang, Ximei Luo, Ying Cheng, Qifeng Song, Jun Wan, Cedric Moore, Hongjun Song, Peng Jin, Jiang Qian, Heng Zhu
Epigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides...
February 4, 2021: Nature Communications
Diana L Bordin, Lisa Lirussi, Hilde Nilsen
The integrity of the genetic information is continuously challenged by numerous genotoxic insults, most frequently in the form of oxidation, alkylation or deamination of the bases that result in DNA damage. These damages compromise the fidelity of the replication, and interfere with the progression and function of the transcription machineries. The DNA damage response (DDR) comprises a series of strategies to deal with DNA damage, including transient transcriptional inhibition, activation of DNA repair pathways and chromatin remodeling...
January 26, 2021: DNA Repair
Jorge Juan Fragío Gil, Elena Grau García, Meritxell Fernández Matilla, Francisco Miguel Ortiz Sanjuan, Regina Rodrigo Nicolás, José Andrés Román Ivorra
OBJECTIVES: DNA hydroxymethylation may be induced by oxidative stress in lupus patients, so we investigated the association between DNA hydroxymethylation and demethylation with the antioxidant response. METHODS: A case-control study was performed including lupus patients and matched healthy controls. Serum concentration of glutathione (GSH), glutathione disulphide (GSSG), superoxide dismutase (SOD) and total antioxidant capacity (TAC), 5-mC and 5-hmC were determined...
January 30, 2021: Medicina Clínica
Jade Pomerleau, Cindy Weidmann, Kelly Coutant, Carolyne-Mary Lowry, Marie-Pier Veilleux, Julie Bérubé, J Richard Wagner, Solange Landreville
DNA methylation and hydroxymethylation represent important epigenetic modifications involved in cell differentiation. DNA hydroxymethylation can be used to classify independent biological samples by tissue type. Relatively little is known regarding the genomic abundance and function of 5-hydroxymethylcytosine (5-hmC) in ocular tissues. The choroid supplies oxygen and nutrients to the outer retina through its dense network of blood vessels. This connective tissue is mainly composed of pigmented melanocytes, and stromal fibroblasts...
January 29, 2021: Experimental Eye Research
Zhijun Huang, Jiyoung Yu, Wei Cui, Benjamin K Johnson, Kyunggon Kim, Gerd P Pfeifer
5-Methylcytosine (5mC) oxidases, the ten-eleven translocation (TET) proteins, initiate DNA demethylation, but it is unclear how 5mC oxidation is regulated. We show that the protein SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) is found in complexes with TET proteins and negatively regulates TET activities. Removal of SMCHD1 from mouse embryonic stem (ES) cells induces DNA hypomethylation, preferentially at SMCHD1 target sites and accumulation of 5-hydroxymethylcytosine (5hmC), along with promoter demethylation and activation of the Dux double-homeobox gene...
January 2021: Science Advances
Z Cai, J Zhang, Y He, L Xia, X Dong, G Chen, Y Zhou, X Hu, S Zhong, Y Wang, H Chen, D Xie, X Liu, J Liu
BACKGROUND: Liquid biopsy based on 5-hydroxymethylcytosine (5hmC) signatures of plasma cell-free DNA (cfDNA) originating from tumor cells provides a novel approach for early diagnosis in hepatocellular carcinoma (HCC). Here, we sought to develop a reliable model using cfDNA 5hmC signatures and protein biomarkers for diagnosis and prognosis of HCC. PATIENTS AND METHODS: We carried out genome-wide 5hmC sequencing of cfDNA samples collected from 165 healthy volunteers, 62 liver cirrhosis (LC) patients and 135 HCC patients...
January 25, 2021: ESMO Open
Yibin Liu, Zhiyuan Hu, Jingfei Cheng, Paulina Siejka-Zielińska, Jinfeng Chen, Masato Inoue, Ahmed Ashour Ahmed, Chun-Xiao Song
Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC...
January 27, 2021: Nature Communications
Kenzo Fujimoto, Wan Licheng, Shigetaka Nakamura
Nucleobase editing is a powerful tool in genetic disease therapy. We have reported the photochemical transition of cytosine to uracil using an ultrafast DNA photo-cross-linking. In this study, we used cytosine derivatives such as methylcytosine, hydroxymethylcytosine, and trifluoromethylcytosine to evaluate the effect of 5-position substitution of cytosine on deamination. The conversion of cytosine to uracil was the fastest, and the conversion of trifluoromethylcytosine to trifluoromethyluracil was the slowest...
January 21, 2021: Bioorganic & Medicinal Chemistry Letters
Anirban Kundu, Sandeep Shelar, Arindam P Ghosh, Mary Ballestas, Richard Kirkman, Hyeyoung Nam, Garrett J Brinkley, Suman Karki, James A Mobley, Sejong Bae, Sooryanarayana Varambally, Sunil Sudarshan
Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes and has been implicated in cancer and aging because of its role as a global epigenetic modifier. TET2 has a large N-terminal domain and a catalytic C-terminal region. Previous reports have demonstrated that the TET2 catalytic domain remains active independently of the N-terminal domain. As such, the function of the N terminus of this large protein remains poorly characterized. Here, using yeast two-hybrid screening, co-immunoprecipitation, and several biochemical assays, we found that several isoforms of the 14-3-3 family of proteins bind TET2...
February 7, 2020: Journal of Biological Chemistry
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