Illuminating how SynGRs liberate gene expression from heterochromatin

The Ansari lab developed a new class of small molecule therapeutics called synthetic gene regulators (SynGRs), one of which, SynTEF1, binds to the FA GAA genetic mutation and specifically increases FXN expression. While the lab has a working model for how SynTEF1 works, the data also indicate that SynTEF1 pushes the boundaries of our knowledge of gene expression. Namely, SynTEF1 improves FXN expression while the gene is considered “off.” Dr Robinson-Thiewes’s proposal is tailored to investigate the scientific quandaries SynTEF1 has illuminated and laid the groundwork to show that SyTEF1 is a viable treatment option for patients. To this end, this investigator has divided her proposal into three questions. First, how does SynTEF1 alleviate FXN’s transcriptional dysregulation? To answer this question, Dr Robinson-Thiewes will use CRISPR/Cas9 genome editing to visualize FXN expression and predict SynTEF1 protein partners in live cells. Second, does SynTEF1 restore mitochondrial function? To answer this question, she will treat FA patient cells with SynTEF1 and analyze mitochondrial health as well as markers of cellular damage. Third, how does long-term exposure to SynTEF1 affect gene expression? To answer this question, she will use two complementary approaches to assess gene expression: RNA sequencing and sequencing that identifies areas of the genome that could be “on”. Answering these questions will advance basic science investigations into gene expression that will be beneficial not only to FA patients but also to countless others who have diseases caused by faulty gene expression.