Cytosine methylation serves as a critical epigenetic mark by modifying DNA-protein interactions that influence transcriptional states and cellular identity. 5-methylcytosine (5-mC) has generally been viewed as a stable covalent modification to DNA;however, the fact that 5-mC can be enzymatically modified to 5-hydroxymethylcytosine (5-hmC) by Tet family proteins through Fe(II) ?-KG-dependent hydroxylation gives a new perspective on the previously observed plasticity in 5-mC-dependent regulatory processes. Epigenetic plasticity in DNA methylation-related regulatory processes influences activity-dependent gene regulation, learning and memory, and repeat-associated transcript expression in the central nervous system (CNS). Hydroxylation of 5-mC to 5-hydroxymethylcytosine (5-hmC) presents a particularly intriguing epigenetic regulatory paradigm in the mammalian brain, where its dynamic regulation is critical. To unravel the biology of 5-hmC, we have developed a highly efficient and selective chemical approach to label and capture 5-hmC, taking advantage of a bacteriophage enzyme that adds a glucose moiety to 5-hmC specifically. Using this technology, we have generated genome-wide maps of 5-hmC in mouse cerebellum and hippocampus during development. Our analyses suggest dynamic regulation of 5-hmC during neurodevelopment. More specifically, we have identified both stable and dynamic DhMRs (Differential 5-hydroxymethylated regions) during neurodevelopment. We have also found that the overall abundance of 5-hmC is negatively correlated with the dosage of MeCP2, which is mutated in Rett syndrome. Intriguingly, loss of Mecp2 leads to the specific reduction of 5-hmC signals at dynamic DhMRs. These data together point to critical roles for 5-hmC-mediated epigenetic regulation in neurodevelopment and human diseases. In this proposed study, using the approach that we have established, we will examine the role of 5-hmC during neurodevelopment. Specifically, we plan to address the following aims: 1) To determine the genome-wide temporal and spatial distribution of 5-hmC during neurodevelopment. 2) To determine how the loss of Mecp2 alters genome-wide 5-hmC modification. 3) To determine the role of Tet proteins in learning and memory. The success of our planned work will define the fundamental role of 5-hmC in neurodevelopment as well as learning and memory.
5-hydroxymethylcytosine (5-hmC) is a newly discovered modified form of cytosine that has been speculated to be an important epigenetic modification during neurodevelopment. We have developed a highly efficient and selective chemical approach to label and capture 5-hmC. Here using this approach we will determine the genome-wide spatial- and temporal-distribution of 5- hmC during neurodevelopment, and determine its potential role(s) in Rett syndrome as well as learning and memory.
|Cheng, Ying; Wang, Zhi-Meng; Tan, Weiqi et al. (2018) Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nat Neurosci 21:1689-1703|
|Yao, Bing; Li, Yujing; Wang, Zhiqin et al. (2018) Active N6-Methyladenine Demethylation by DMAD Regulates Gene Expression by Coordinating with Polycomb Protein in Neurons. Mol Cell 71:848-857.e6|
|Cheng, Ying; Li, Ziyi; Manupipatpong, Sasicha et al. (2018) 5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder. Hum Mol Genet 27:2955-2964|
|Yao, Bing; Jin, Peng (2018) A unique epigenomic landscape defines the characteristics and differentiation potentials of glioma stem cells. Genome Biol 19:51|
|Kim, Hyerim; Wang, Xudong; Jin, Peng (2018) Developing DNA methylation-based diagnostic biomarkers. J Genet Genomics 45:87-97|
|Pan, Feng; Wingo, Thomas S; Zhao, Zhigang et al. (2017) Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells. Nat Commun 8:15102|
|Li, Xuekun; Yao, Bing; Chen, Li et al. (2017) Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis. Nat Commun 8:15903|
|Zhao, Jinying; Zhu, Yun; Yang, Jingyun et al. (2017) A genome-wide profiling of brain DNA hydroxymethylation in Alzheimer's disease. Alzheimers Dement 13:674-688|
|Yao, Bing; Cheng, Ying; Wang, Zhiqin et al. (2017) DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress. Nat Commun 8:1122|
|Li, Liping; Zang, Liqun; Zhang, Feiran et al. (2017) Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 26:2398-2411|
Showing the most recent 10 out of 43 publications