Interplay between cardiac transcription factors and non-coding RNAs in predisposing to atrial fibrillation

Abstract

There is growing evidence that putative gene regulatory networks including cardio-enriched transcription factors, such as PITX2, TBX5, ZFHX3, and SHOX2, and their effector/target genes along with downstream non-coding RNAs can play a potentially important role in the process of adaptive and maladaptive atrial rhythm remodeling. In turn, expression of atrial fibrillation-associated transcription factors is under the control of upstream regulatory non-coding RNAs. This review broadly explores gene regulatory mechanisms associated with susceptibility to atrial fibrillation-with key examples from both animal models and patients-within the context of both cardiac transcription factors and non-coding RNAs. These two systems appear to have multiple levels of cross-regulation and act coordinately to achieve effective control of atrial rhythm effector gene expression. Perturbations of a dynamic expression balance between transcription factors and corresponding non-coding RNAs can provoke the development or promote the progression of atrial fibrillation. We also outline deficiencies in current models and discuss ongoing studies to clarify remaining mechanistic questions. An understanding of the function of transcription factors and non-coding RNAs in gene regulatory networks associated with atrial fibrillation risk will enable the development of innovative therapeutic strategies.

The roles of long noncoding RNAs in atrial fibrillation

“…Additionally, TCONS_00075467 adsorbed miR-328 to derepress the downstream target gene L-type voltage-dependent calcium channel subunit α1C expression to alleviate AF electrical remodeling. Several cardiac-specific transcription factors, such as paired-like homeodomain transcription factor 2 (PITX2) and T-Box transcription factor 5 (TBX5), have been shown to be involved in the regulation of ion channel genes and play a role in AF, with decreasing PITX2 level shortening atrial effective refractory period [ 34 , 35 ]. Gore-Panter et al identified a lncRNA gene localized upstream to the PITX2 gene, called PITX2 adjacent non-coding RNA (PANCR) [ 36 ].…”

A narrative review of non-coding RNAs in atrial fibrillation: potential therapeutic targets and molecular mechanisms

“…A growing number of evidence suggests that putative gene regulatory networks (GRNs), including cardiac-enriched transcription factors (TFs) and its target genes, can play a potentially important role in the process of adaptive and maladaptive atrial rhythm remodeling (90)(91)(92). In addition, the human genome-wide association studies (GWAS) have successfully identified more than 100 genetic sites associated with atrial fibrillation, including genes encoding cardioenriched TFs (93,94).…”

Epigenetics in atrial fibrillation: A reappraisal

“…Further, genes related to structural abnormalities are regulated by mir-21, mir-26, mir-29b, mir-30, mir-133 and mir-590 45 . Perturbations of a dynamic expression balance between TFs, such as PITX2, TBX5, ZFHX3, and SHOX2, and corresponding miRNAs may predispose to AF 46 . The possibility of the complex interaction among circRNAs, miRNAs, and mRNAs is also proposed in AF patients 47 .…”