PANCR, the PITX2 Adjacent Noncoding RNA, Is Expressed in Human Left Atria and Regulates PITX2c Expression.
PANCR, the PITX2 Adjacent Noncoding RNA, Is Expressed in Human Left Atria and Regulates PITX2c Expression.
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DOI：
10.1161/circep.115.003197
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Smith JD
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文献类型：
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作者：
Gore-Panter SR;Hsu J;Barnard J;Moravec CS;Van Wagoner DR;Chung MK;Smith JD
全基因组研究表明，染色体 4q25 的遗传变异构成了与房颤 (AF)（最常见的心律失常）相关的最强位点。然而，这种关联背后的机制尚不清楚。我们的目标是找到并表征染色体 4q25 AF 风险位点中左心房表达的转录本，这些转录本可能在 AF 发病机制中发挥作用。对人类左/右对进行的 RNA 测序鉴定出与 PITX2 基因相邻的基因间长非编码 RNA (lncRNA)，我们将其命名为 PANCR（PITX2 相邻非编码 RNA）。在人体组织筛选中，PANCR 在左心房和眼睛中特异性表达，而在心脏的其他腔室中没有表达。 233 份人类左心耳样本中 PANCR 和 PITX2c RNA 的水平高度相关。 PANCR 水平与心房节律状态或染色体 4q25 AF 风险变异的基因型无关。 PANCR 和 PITX2c RNA 在人胚胎干细胞分化为心肌细胞的早期被诱导。由于lncRNA通常控制基因表达，我们进行了siRNA介导的PANCR敲低；而且，这种治疗抑制了 PITX2c 表达，并模拟了 PITX2c 敲低对整体 mRNA 和 miRNA 表达的影响。细胞分级分离研究表明 PANCR 主要位于细胞质中。 PANCR 和 PITX2c 在心肌细胞从干细胞分化的早期协同表达。 PANCR 敲低降低了分化心肌细胞中 PITX2c 的表达，以类似于 PITX2c 敲低的方式改变转录组。
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. 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. 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.