All Grown Up: 5-hmC Changes in Human Fetus and Adult Cerebellum
The role of DNA methylation in healthy embryonic and postnatal neurological development has been well established in recent years. In addition to 5-methylcytosine (5-mC), high levels of 5-hydroxymethylcystosine (5-hmC) have also been detected in brain and other neurological tissue. Several studies have shown that defects in the ten-eleven translocation (TET) proteins, which catalyze the conversion of 5-mC to 5-hmC, are associated with regulatory dysfunction in embryonic stem cells, thus establishing a relationship between 5-hmC and developmental processes. However, the function of 5-hmC modifications during human development is still widely unknown.
In a recent study, Wang et al. examined5-hmC levels in human cerebellum. Using dot blot and capturing methods, they reported that genomic 5-hmC levels are 42% higher in adult cerebellum compared to fetal cerebellum. By genome profiling, they observed 5-hmC-enriched regions specific to either adult or fetal brain. The majority of 5-hmC modifications were associated with genes and localized at exons and 5’ UTR regions, as opposed to introns or intergenic regions, however more fetal regions were also associated with transcriptional start sites. The authors also reported that fetal cerebellum 5-hmC levels and distributions were similar to those seen in HI human embryonic stem cells (HI hESCs), but that adult cerebellum 5-hmC patterns varied significantly from HI hESCs. Based on the findings of a previous paper the group published regarding 5-hmC enrichment in mouse cerebellum (Szulwach et al., 2011), the authors examined 5-hmC enrichment in neurodevelopmental genes. They observed 5-hmC enrichment in mRNAs regulated by fragile X mental retardation protein (FMRP), a protein that can inhibit translation of mRNAs involved in mediating neuron plasticity and is associated with fragile X syndrome (FSX) or autism spectrum disorder (ASD).
While it is still too early to draw concrete conclusions, the results from this study suggest a dynamic relationship between 5-hmC and human brain development. These data imply that 5-hmC levels increase during cerebellum development and that aberrant 5-hmC modifications may influence development and even contribute to disease, such as FXS or ASD. As more knowledge is acquired about the role 5-mC and 5-hmC modifications in neurological development, the better understanding we gain regarding neurological diseases and potential therapies.
Wang T, Pan Q, Lin L, Szulwach KE, Song CX, He C, Wu H, Warren ST, Jin P, Duan R, & Li X (2012). Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum. Human molecular genetics, 21 (26), 5500-10 PMID: 23042784