Authors: Braxton Bird
Mentors: Sarah Franklin
Insitution: University of Utah
Heart disease ends the lives of nearly 700,000 people each year and has been the leading cause of death in the United States since 1950. Around this time researchers discovered that some modifications involving our genetic code could be altered to affect gene expression but leaves the DNA intact, which was later termed epigenetics. Today we’ve discovered that these epigenetic modifications, including post translational modifications (PTMS), regulate genes linked to cardiovascular disease. We recently examined the histone lysine methyltransferase SETD7, which is most prominently known for its ability to methylate histone H3K4. SETD7’s expression is upregulated in multiple types of heart disease in both humans and mice and is essential for cardiomyocyte differentiation in embryonic development. In addition to its ability to methylated H3K4, SETD7 has been shown to methylate 8 other histone residues. To further characterize the histone residues methylated by SETD7, we carried out an unbiased analysis of lysine residues methylated by SETD7 using an in vitro methyltransferase assay coupled with tandem mass spectrometry. We hypothesized that SETD7 may modify additional sites than those that have previously been identified. Our analysis determined that SETD7 monomethylates two novel residues on histone H3: lysine 36 (K36) and lysine 122 (K122). These sites of modification were also confirmed by western blotting for site specific antibodies to these methylation marks. Although our understanding of both these residues is limited, we do know that K36 methylation is linked to DNA replication and genomic stability while K122 methylation is downregulated in drug-resistant MCF-7/ADR cancer cells. These two novel methylation sites suggest that this lysine methyltransferase plays a more complex role in regulating epigenetic modifications and gene expression than previously recognized. Although the identification of this new enzymatic activity for SETD7 is important for understanding the dynamic function of methyltransferases, additional studies will be necessary to fully elucidate the role of SETD7 in cardiac physiology and gene regulation.