@article{Regulatory:5248,
      recid = {5248},
      author = {Lazarevic, Sonja},
      title = {Defining Gene Regulatory Networks in Cardiac Rhythm and  Disease },
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2022-12},
      pages = {158},
      abstract = {Atrial fibrillation (AF) is the most common type of  cardiac arrhythmia, characterized by an irregular heartbeat  due to uncoordinated electrical activity in the atria. The  Tbx5 locus has been implicated by genome wide association  studies (GWAS), and our laboratory has previously shown  that the absence of Tbx5 leads to spontaneous and sustained  AF. We will utilize this Tbx5-deficient mouse model to  further characterize the regulatory mechanisms important  for cardiac rhythm and the molecular mechanisms driving the  pathophysiology of atrial fibrillation.Cardiac rhythm is a  dose-sensitive physiologic process, therefore stable gene  expression is imperative for proper cardiac function.  Precise gene regulation is reliant on feedback mechanisms  to maintain accurate gene expression, and miRNAs are a  canonical feedback mechanism for steady gene expression. In  Chapter 1, our laboratory performed small RNA profiling of  Tbx5-deficient mice to define candidate miRNAs involved in  the TBX5-dependent gene regulatory network important for  the maintenance of cardiac rhythm. Many of the miRNAs  identified were interrogated in a high-throughput screen,  which linked arrhythmogenic phenotypes to several miRNAs.  Whole mouse and cellular electrophysiology studies were  focused on a single miRNA candidate, miR-10b, and  demonstrated its mis-regulation leads to atrial  fibrillation susceptibility. This work supports a model  where TBX5 regulates the expression of miRNAs critical for  maintaining appropriate gene expression levels important in  cardiac rhythm.
Atrial fibrillation also has a strong  epidemiologic link with heart failure, as these two cardiac  diseases are associated with increased incidence of each  other. In Chapter 2, we revealed remarkable correlation  between the differentially expressed genes in the atria of  AF and heart failure mouse models, and identified shared  transcription factors as candidates important in driving  the pathophysiology of cardiac disease. We also identified  the conservation of differential ncRNA transcripts in both  of these disparate disease models. Based on the knowledge  that noncoding RNAs (ncRNAs) are transcribed from  regulatory elements, it supports the paradigm of a common  disease-specific gene regulatory network that mediates the  physiologic consequences of disease. These differential  non-coding RNA transcripts identified a TBX5-dependent  candidate regulatory element downstream of Klf15, an  important regulator in cardiac hypertrophy. We also  identified a ncRNA transcript upstream of Sox9 that is  up-regulated in both disease models, and may uncover a  disease-response essential for coping with atrial  dysfunction. In summary, our studies have identified  crucial transcriptional changes in atrial fibrillation and  heart failure, along with the shared regulatory mechanisms  critical in driving these changes. 
	Finally, in Chapter 4  we performed a time course deletion of Tbx5 in an effort to  identify the earliest transcriptional changes in this  atrial fibrillation mouse model. Interestingly, the removal  of Tbx5 leads to an early response at Day 3 and Day 6,  which is very different from the response at Day 10 and Day  17 of the time course. In an effort to identify significant  gene expression changes between Tbx5 KO and WT throughout  the time course we performed maSigPro analysis, which has  provided us with candidate genes important in driving the  pathophysiology of atrial fibrillation.},
      url = {http://knowledge.uchicago.edu/record/5248},
      doi = {https://doi.org/10.6082/uchicago.5248},
}