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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS079625-02
Application #
8463268
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Mamounas, Laura
Project Start
2012-08-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$320,604
Indirect Cost
$88,218
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M et al. (2015) Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice. Cell Rep 13:1692-704

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