Grant: Project Grant - PA: Epigenetics/epigenomics in human health or disease

Huntington's disease (HD) is a brain disease caused by an expansion of CAG nucleotide triplet in the huntingtin gene. The longer the CAG expansion, the earlier the onset of the disease. However, this DNA mutation does not fully explain the variability in the age-of-onset, nor fully predicts disease severity. There are numerous other important questions related to HD which need to be addressed. For instance, the average age of disease onset is 45 years, which means that there are decades of "healthy periods" in HD patients despite the fact that the "toxic" gene and its protein product are present in the brain all the while. Another mystery is why the disease only affects some brain cells, while other cells in the same brain are spared. All these fundamental HD questions could be explained by epigenetic factors, which are chemical modifications to DNA that regulate genes. Without proper epigenetic "instructions", the genomic "machinery" cannot function properly and could even be harmful. Epigenetic "instructions" are distinct in different brain regions, which could be why problems arise in some regions but not in others. In addition, epigenetic marks can change in aging cells; it may take extended periods for slow epigenetic degradation to reach a critical mass of malfunction resulting in HD symptoms. In the proposed project, we will use a mouse model of HD to investigate the epigenetic "instructions" within brain cells that are sensitive to (and spared from) the disease. We plan to investigate how epigenomes "age" differently in the brains of HD mice compared to normal mice. For the first time in brain disease studies, we will test if pathological epigenetic aging in HD is related to, and maybe even caused by, another major biological regulator - the brain's internal clock. This unique study of HD epigenomes may lead to insights pertaining to the origin and fundamental mechanisms of brain degeneration.