Huntington’s disease (HD) is an inherited, progressive neurodegenerative disorder characterized by chorea, gradual but inexorable cognitive decline, and psychiatric disturbances. There is no cure for this devastating neurological disease. Selective degeneration of striatal neurons is a pathologic hallmark of HD, however, the exact mechanism(s) behind the selective neuronal loss of striatal medium spiny neuron is still unclear. DNA methylation constitutes a critical epigenetic modification that plays pivotal roles in chromatin structure remolding, gene silencing, embryonic development, differentiation and maintenance of cellular identity. Recent studies demonstrate that 5mC can be converted to 5-hydroxymethylcytosine (5-hmC) which may represent a new epigenetic modification of cytosine. While the dynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington’s disease (HD).

Molecular and Cellular Neuroscience group led by Dr. Tie-Shan Tang, Institute of Zoology, Chinese Academy of Sciences, has observeda marked reduction of 5-hmCsignalin YAC128 (yeast artificial chromosome transgene with 128 CAG repeats) HD mouse brain tissues when compared with age-matched wild type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains during postnatal development. Genome-wide distribution analysis of 5-hmC further confirmed the diminishment of 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions. Intriguingly, they have identi？ed disease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuity pathway analysis of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/b-catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway etc) could be important for the onset of HD.These results indicate that loss of the 5-hmC marker is a novel epigenetic feature in Huntington’s disease, and that this aberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain. This study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscape may have the potential to slow/halt the progression of HD.

This work was published in Human Molecular Genetics ahead of print on May 12, 2013, doi: 10.1093/hmg/ddt214

http://hmg.oxfordjournals.org/content/early/2013/05/12/hmg.ddt214.short