The study by Mellen et al. (2013) investigates the distribution and function of 5-hydroxymethylcytosine (5hmC) in the nervous system, particularly in neurons. They find that 5hmC is highly enriched in active genes and accessible chromatin within the brain, while 5-methylcytosine (5mC) is depleted in gene bodies. The authors identify methyl-CpG binding protein 2 (MeCP2) as the primary 5hmC binding protein in the brain, showing that MeCP2 binds both 5hmC and 5mC with high affinity. The R133C mutation in the MeCP2 methyl-CpG binding domain preferentially inhibits 5hmC binding. Despite this, loss of MeCP2 does not alter the genomic distribution of 5hmC. These findings suggest that 5hmC and MeCP2 form a novel, cell-specific epigenetic mechanism for regulating chromatin structure and gene expression in the mammalian nervous system, providing insights into the pathophysiology of Rett Syndrome (RTT).The study by Mellen et al. (2013) investigates the distribution and function of 5-hydroxymethylcytosine (5hmC) in the nervous system, particularly in neurons. They find that 5hmC is highly enriched in active genes and accessible chromatin within the brain, while 5-methylcytosine (5mC) is depleted in gene bodies. The authors identify methyl-CpG binding protein 2 (MeCP2) as the primary 5hmC binding protein in the brain, showing that MeCP2 binds both 5hmC and 5mC with high affinity. The R133C mutation in the MeCP2 methyl-CpG binding domain preferentially inhibits 5hmC binding. Despite this, loss of MeCP2 does not alter the genomic distribution of 5hmC. These findings suggest that 5hmC and MeCP2 form a novel, cell-specific epigenetic mechanism for regulating chromatin structure and gene expression in the mammalian nervous system, providing insights into the pathophysiology of Rett Syndrome (RTT).