Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation

Abstract

Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. In this review, we discuss a transcriptional regulatory network model for AF defined by effector genes in Genome-wide association studies loci. We describe the current state of the field regarding the identification and function of AF-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. We illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact AF risk. Last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.

Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

“…In addition, recent findings in a mouse model that deactivated the enhancer region of Pitx2c found Bmp10 to be one of the most upregulated genes ( 37 ). These results suggest that a common repressor/enhancer transcriptional network may exist between Bmp10 and Pitx2 whereby the loss of one of these genes results in the reciprocal upregulation of the other ( 18 , 38 ). Such findings are plausible given that PITX2 is known to be a key regulator of “leftness” in the heart during development ( 36 , 39 ) and BMP10 is a right atrial gene ( 11 , 40 ).…”

“…PITX2 functions as an essential cardiac transcriptional factor, possibly acting within a network of transcriptional regulation ( 18 ). Reduced PITX2 expression results in congenital heart diseases ( 12 , 34 ) and cardiac arrhythmogenic defects ( 14 ).…”

“…While cellular expression of such variants can reduce ( 35 ) or increase PITX2 levels ( 49 ), the control of PITX2 in the left atrium of patients will be modified by transcriptional and epigenetic regulation of PITX2 , along with other factors (reviewed in ref. 18 ). The partial redundancy in the regulation of atrial gene expression ( 18 ) can further mitigate the AF drivers associated with reduced PITX2 .…”

“… 18 ). The partial redundancy in the regulation of atrial gene expression ( 18 ) can further mitigate the AF drivers associated with reduced PITX2 .…”

“…Gene expression analyses highlight that Pitx2c controls expression of ion channels and desmosomal genes ( 12 , 16 , 17 ). These alterations in gene expression are brought about by an altered balance in the atrial network of transcription factors ( 18 , 19 ). Taken together, these findings suggest that reduced left atrial PITX2 could predispose patients to recurrent AF after AF ablation.…”