PANCR, the PITX2 Adjacent Noncoding RNA, Is Expressed in Human Left Atria and Regulates PITX2c Expression

Abstract

Background Genome-wide studies reveal that genetic variants at chromosome 4q25 constitute the strongest locus associated with atrial fibrillation (AF), the most frequent arrhythmia. However, the mechanisms underlying this association are unknown. Our goal is to find and characterize left atrial expressed transcripts in the chromosome 4q25 AF risk locus that may play a role in AF pathogenesis. Methods and Results RNA sequencing performed on human left/right pairs identified an intergenic long noncoding RNA (lncRNA) adjacent to the PITX2 gene, which we have named PANCR (PITX2 adjacent noncoding RNA). In a human tissue screen, PANCR was expressed specifically in the left atria and eye, and in no other chambers of the heart. The levels of PANCR and PITX2c RNAs were highly correlated in 233 human left atrial appendage samples. PANCR levels were not associated with either atrial rhythm status or the genotypes of the chromosome 4q25 AF risk variants. Both PANCR and PITX2c RNAs were induced early during differentiation of human embryonic stem cells into cardiomyocytes. Since lncRNAs often control gene expression, we performed siRNA-mediated knockdown of PANCR; and, this treatment repressed PITX2c expression and mimicked the effects of PITX2c knockdown on global mRNA and miRNA expression. Cell fractionation studies demonstrate that PANCR is primarily localized in the cytoplasm. Conclusions PANCR and PITX2c are coordinately expressed early during cardiomyocyte differentiation from stem cells. PANCR knockdown decreased PITX2c expression in differentiated cardiomyocytes, altering the transcriptome in a manner similar to PITX2c knockdown.

DNA Methylation of PITX2 and PANCR Is Prognostic for Overall Survival in Patients with Resected Adenocarcinomas of the Biliary Tract

“…A positive correlation of hypermethylated gene body with an increased gene expression has been reported by several groups [45–47]. One might infer that PANCR expression is elevated as well as PITX2c ; besides, a positive correlation of expression was observed in human adult left atria tissue [30]. …”

“…This gene is referred to as PANCR ( PITX2 adjacent noncoding RNA) and is expressed mainly in the left atrium of the human heart. Functionally, it has been suggested that PANCR co-regulates PITX2c expression during cardiomyocyte differentiation [30]. Because of numerous known functions of lncRNA in a range of cellular processes, dysregulation of lncRNAs not surprisingly has been identified as a hallmark in various benign and malignant diseases including BTC (for review see ref.…”

Pitx2 Adjacent Noncoding RNA

“…3,9 On the basis of these insights and the impact of gene variants on chromosome 4q25 for AF, the genetic predisposition to AF has been identified as a promising candidate to develop personalized approaches to AF management. 10 In this issue of Circulation Arrhythmia and Electrophysiology, Gore-Panter et al 11 describe a new regulator of PITX2c expression in the left atrium: They identified a long noncoding RNA adjacent to the PITX2 gene (Pitx2 adjacent noncoding RNA [PANCR]). PANCR positively correlates with PITX2c mRNA expression in human patient left atrial appendage samples and knock down of PANCR in H9-derived cardiomyocytes depletes cells of PITX2c.…”

“…12,13 But is this really surprising? All tissue samples available to Gore-Panter et al 11 -similar to what is available to other research groups-were obtained from patients requiring open-heart surgery for severe heart disease (usually coronary artery bypass grafting and valve surgery). It is entirely unknown how atrial PITX2 (and PANCR) expression is altered by pressure overload, diabetes mellitus, hypoxia/ischemia, inflammation, autonomic dysfunction, or by the stress of open-heart surgery.…”

“…Gore-Panter et al 11 show that PANCR, a long, noncoding RNA, is expressed in the human left atrium and that it is a potent regulator of PITX2 expression. This is important information that can help to guide the quest to understand the mechanisms mediating the genetic predisposition to AF.…”