Huntington’s disease (HD) is a neurodegenerative disorder that involves the death of medium spiny neurons (MSN) in the caudate-putamen and is caused by a CAG trinucleotide repeat expansion in the huntingtin gene. How mutant huntingtin causes neuronal death is still unclear, but many cellular mechanisms have been linked to disease pathogenesis, such as: protein aggregation, abnormal gene expression, elevated oxidative stress and DNA damage. Recent studies have shown that an epigenetic complex known as polycomb repressive complex 2 (PRC2) plays a pivotal role in gene expression by regulating histone H3 trimethylation and might be linked to HD pathogenesis. Also, it was shown that PRC2 is essential for the maintenance of neuronal integrity. The PRC2 complex is composed of several subunits, including one of two catalytic subunits, EZH1 or EZH2. Thus far, few studies in neurons have examined the differential cellular role of PRC complexes that contain either EZH1 or EZH2 proteins. However, preliminary data has shown that their expression differs during the development of the nervous system and at adulthood. In this project, we hypothesized that the PRC2-EZH1 complex may have a different role than the PRC2-EZH2 complex with regard to neuronal integrity and modulating HD pathogenesis. To verify this hypothesis, we will study the role of PRC2-EZH1 and PRC2-EZH2 in neuronal-like cells under different stress conditions and in HD cellular models. If this project is successful, we will have increased our understanding of the role of PRC2 in neuronal cells and potentially open new research avenues for HD pathogenesis.
PROJECT: Evaluation of EZH1 and EZH2 function in neuronal cell viability
The Broad Summer Research Program was challenging, and also immensely rewarding. My mentor was instrumental in sparking my scientific curiosity and guiding me in becoming independent and efficient in the lab. My experience at the Broad and Picower Institutes have given me newfound confidence in my potential as a leader in health care and in the scientific community.