The transcriptional basis of homeostasis and disease is implied by the non-coding nature of genetic variation identified by GWAS. Functional genomic approaches to unveil the gene regulatory networks (GRNs) relevant to disease is therefore a high priority. Most models for transcriptional dysregulation presume that perturbation of a wild-type GRN causes disease risk. For example, the T-box transcription factor, TBX5, is essential for atrial rhythm homeostasis and directly drives a physiologically relevant GRN composed of cardiac channel genes. Alternatively, examination of the upregulated genes after the deletion of Tbx5 implicates the activation of a disease-specific GRN. Using TF-dependent noncoding RNA (ncRNA) profiling, through the differential deep ncRNA sequencing from atria of wild-type and Tbx5 mutant mice, we focused on the ncRNAs that were only active following the deletion of TBX5. Therefore, we identified putative TBX5-dependent enhancers, based on knowledge that ncRNAs can identify transcription at regulatory elements. We hypothesized that these regulatory elements may reveal disease-response enhancers, essential for coping with atrial dysfunction. We sought to identify the cell-specificity of these enhancers and therefore generated cell-type specific ATAC-seq datasets for left atrial tissue, cardiac fibroblasts, and cardiomyocytes, then overlapped each dataset with the ncRNAs. These candidate regulatory elements included a putative enhancer upstream of Sox9, a known modulator of cardiac fibrosis, along with other cardiac stress-response pathways, including mediators of TGF-β signaling. The ncRNA candidate is expressed in isolated cardiac fibroblasts treated with TGF-β, and the enhancer demonstrated luciferase activation in fibroblasts. To examine the hypothesis that the disease-acquired GRN in TBX5 mutant atria may be generalizable to other cardiac insults, we examined the transcriptional changes occurring in the left atria of a Transverse Aortic Constriction (TAC) mouse model. We revealed remarkable correlation between the differentially expressed genes between these disparate disease models. We also performed differential ncRNA profiling from this pressure overload mouse model, and identified the conservation of acquired ncRNAs when compared to the cardiac arrhythmia mouse model. The conservation of the transcriptional analysis and ncRNA candidates supports the paradigm of a common disease-specific GRN that mediates and may participate in the physiologic consequences of disease.