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; Bernstein, Alison; Chen, Dahua et al. (2015) 5-Hydroxymethylcytosine: A new player in brain disorders? Exp Neurol 268:9-Mar|
|Yao, Bing; Jin, Peng (2014) Unlocking epigenetic codes in neurogenesis. Genes Dev 28:1253-71|
|Duan, Ranhui; Sharma, Sumeet; Xia, Qiuping et al. (2014) Towards understanding RNA-mediated neurological disorders. J Genet Genomics 41:473-84|
|Szulwach, Keith E; Jin, Peng (2014) Integrating DNA methylation dynamics into a framework for understanding epigenetic codes. Bioessays 36:107-17|
|Yao, Bing; Lin, Li; Street, R Craig et al. (2014) Genome-wide alteration of 5-hydroxymethylcytosine in a mouse model of fragile X-associated tremor/ataxia syndrome. Hum Mol Genet 23:1095-107|
|Irier, Hasan; Street, R Craig; Dave, Ronak et al. (2014) Environmental enrichment modulates 5-hydroxymethylcytosine dynamics in hippocampus. Genomics 104:376-82|
|Yao, Bing; Jin, Peng (2014) Cytosine modifications in neurodevelopment and diseases. Cell Mol Life Sci 71:405-18|
|Zhu, Gengzhen; Li, Yujing; Zhu, Fei et al. (2014) Coordination of engineered factors with TET1/2 promotes early-stage epigenetic modification during somatic cell reprogramming. Stem Cell Reports 2:253-61|
|Zhang, Wenxin; Cheng, Ying; Li, Yujing et al. (2014) A feed-forward mechanism involving Drosophila fragile X mental retardation protein triggers a replication stress-induced DNA damage response. Hum Mol Genet 23:5188-96|
|Wang, Tao; Warren, Stephen T; Jin, Peng (2013) Toward pluripotency by reprogramming: mechanisms and application. Protein Cell 4:820-32|
Showing the most recent 10 out of 14 publications