April is Autism Awareness Month: Increased levels of 5-hmC may influence gene regulation in Autism Spectrum Disorder
The prevalence of Autism Spectrum Disorder (ASD) has increased by roughly 30% since 2012. The CDC recently reported that one in 68 children in the United States is affected by ASD, compared to one in 88 just two years ago. This enhanced occurrence could be attributed to advancements in the detection and diagnosis, increased awareness, or simply that the number of ASD patients is on the rise. Regardless, it is a major problem affecting our nation’s youth. ASD is classified as a neurodevelopmental disorder that impacts behavior, social interactions, and communication skills and can range from mild to severe depending on the individual. There are many factors believed to influence ASD including; environmental, genetic and recently discovered epigenetic regulations. Earlier this year, Zhubi et al. published a paper regarding the importance of 5- hydroxymethylcytosine (5-hmc) in mediating the complex interaction between methyl CpG binding protein-2 (MeCP2) and two genes, glutamic acid decraboxylase (GAD1) and Reelin (RELN), each of which has been shown to be decreased in the brain of ASD patients.
The authors compared cerebellar cortex samples from a control and ASD group. They discovered the MeCP2 was binding to the promoter regions of GAD1 and RELN rather than the gene body, and MeCP2 binding to the promoters decreased mRNA expression of both GAD1 and RELN in the ASD samples. The authors also determined that MeCP2 mRNA expression was increased in the ASD group. In addition, they found that the levels of 5-hmC, and not 5-methylcystosine (5-mC), were increased in the promoter region of GAD1 and RELN. These results suggested some sort of relationship between 5-hmC, MeCP2 and the regulation of GAD1 and RELN in ASD. The authors sought to explain this relationship by examining TET1, an enzyme involved in the demethylation of 5-mC to 5-hmC, using Tet-assisted bisulfite pyrosequencing (TAB-Seq) and chromatin immunoprecipitations (ChIP). Using TAB-Seq, they determined that 5-hmC was enriched in specific CpG positions in the ASD group, where 5-mC was not detected. In contrast, the control group showed 5-mC levels enriched at certain CpG locations and not 5-hmC. ChIP results determined increased binding of TET1 to GAD1 and RELN. This also corresponded with an increase in TET1 mRNA levels in ASD samples.
With April being Autism Awareness Month, what better time to shed light on new research that is occurring in the field. This paper supports the expanding and complex role of epigenetic regulation in ASD. Specifically, these data contribute to other findings that MeCP2 role in transcriptional regulation in ASD is more complex than previously thought, and that the role of 5-hmC may serve to promote, or in this case inhibit expression of certain genes. Though this study focuses on a single protein and its role in regulating gene expression, it contributes to an expanding pool of knowledge that can hopefully help diagnose and treat ASD in the future.
Zhubi A, Chen Y, Dong E, Cook EH, Guidotti A, & Grayson DR (2014). Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum. Translational psychiatry, 4 PMID: 24448211