Autism is comprised of a clinically heterogeneous group of disorders, collectively termed """"""""autism spectrum disorders"""""""" (ASD), which share common features of impaired social relationship, impaired language and communication, and limited range of interests and behavior. Although monogenic disorders collectively only account for a minority of autism cases (10-15%), the molecular alterations in these disorders could reveal common pathogenic pathways shared by ASDs. Cytosine methylation serves as a critical epigenetic mark by modifying DNA-protein interactions that influence transcriptional states and cellular identity. 5-methylcytosine (5mC) has generally been viewed as a stable covalent modification to DNA;however, the fact that 5-mC can be enzymatically modified to 5-hydroxymethylcytosine (5hmC) by Tet family proteins through Fe(II) alpha-KG- dependent hydroxylation gives a new perspective on the previously observed plasticity in 5mC-dependent regulatory processes. Epigenetic plasticity in DNA methylation-related regulatory processes influences activity- dependent gene regulation and learning and memory in the central nervous system (CNS). Hydroxylation of 5mC to 5hmC presents a particularly intriguing epigenetic regulatory paradigm in the mammalian brain, where its dynamic regulation is critical. To unravel the biology of 5hmC, we have developed approaches to map genome-wide 5hmC distribution. Using these technologies, we generated genome-wide maps of 5hmC during brain development, providing a detailed epigenomic view of regulated 5hmC in CNS. Our analyses suggest a highly dynamic regulation of 5hmC during neurodevelopment. More specifically, we have identified both stable and dynamic DhMRs (Differential 5-hydroxymethylated regions) during neurodevelopment. Surprisingly DhMRs are highly enriched in the genes that have been implicated in autism. We have also found that the loss of Mecp2 leads to the specific reduction of 5hmC signals at dynamic DhMRs of cerebellum. More intriguingly, we have recently found that the loss of Fmr1, responsible for fragile X syndrome, could alter the 5hmC signals at dynamic DhMRs in mice as well. These data suggest that 5hmC-mediated epigenetic regulation may broadly impact brain development, and its dysregulation could contribute to autism. In this proposal, we will determine whether there is consistent alteration of 5hmC modification at dynamic DhMRs among mouse models of ASD-linked monogenic disorders, and determine the functional role(s) of Tet-mediated epigenetic modulation in ASD-linked monogenic disorders.

Public Health Relevance

Several disorders caused by single-gene mutations, such as Fragile X syndrome and Rett syndrome, are associated with autism, reflecting a greatly increased risk of autism conferred by the mutations. Although these monogenic disorders collectively only account for a minority of autism cases (10-15%), the molecular alterations in these disorders could reveal common pathogenic pathways shared by autism. In this proposed study, we will investigate whether 5hmC and Tet-mediated epigenetic modulation could contribute to the molecular pathogenesis of autism-linked monogenic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH102690-01
Application #
8623843
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2014-04-01
Project End
2018-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$684,145
Indirect Cost
$222,797
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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
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
Yoon, Ki-Jun; Ringeling, Francisca Rojas; Vissers, Caroline et al. (2017) Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell 171:877-889.e17
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
Nott, Alexi; Cheng, Jemmie; Gao, Fan et al. (2016) Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat Neurosci 19:1497-1505

Showing the most recent 10 out of 45 publications