Talk abstracts
Talk on Thursday 03:45-04:00pm submitted by Jenna Thuma
Troponin enhanceropathies: a novel role for the troponin genes
Jenna Thuma (Biophysics Graduate Program), Madhoolika Bisht (Physiology and Cell Biology), Yvette Wang (Physiology and Cell Biology), Jordan King , Brandon Biesiadecki (Physiology and Cell Biology), Jon Davis (Physiology and Cell Biology)
Abstract:
Striated muscle contraction is regulated by the troponin complex which consists of three proteins: troponin C (TnC), troponin I (TnI), and troponin T (TnT). Cardiac troponins protein role in the heart is well known and documented; however, we are proposing a novel role for the cardiac troponins at the DNA level. DNA regulatory elements are important regions that control cell and time specific gene expression. These types of elements are generally found intergenically or intronically, but rarely they can also be found within exons. Shockingly, we found evidence that all three cardiac troponin genes contain these exonic DNA regulatory elements. Thus, any nucleotide mutation in their exonic DNA regulatory element would not only change protein structure and function in the heart, but also the function of the regulatory element. This could result in altered expression of the genes that the element controls. Although we believe this occurs in all three subunits, here we focus on the inhibitory subunit, TnI (Tnni3). First, we confirmed regulatory activity by luciferase assays then used chromosome conformation capture databases to determine the regulatory targets of this element. The regulatory elements within cardiac TnI appear to interact with two genes, slow skeletal TnT (Tnnt1) and Dnaaf3. TnI knockout mice have diaphragm weakness consistent with TnT dysregulation, whereas we observe both gross internal organ and sperm abnormalities consistent with Dnaaf3 dysregulation. Furthermore, we see the same abnormal anatomy and corresponding differential expression of Tnnt1 in skeletal muscles and Dnaaf3 in the reproductive organs by qPCR in a KI model (only different by 4nt). Thus, we are proposing a novel DNA regulatory role for the cardiac troponins, independent of their protein function, that, when mutated, may cause non-cardiac disease.
Keywords: DNA regulation, Physiology