Research purpose

The sinus node (SN) is the heart's primary pacemaker. Key ion channels (mainly the funny channel, HCN4) and Ca²⁺-handling proteins in the SN are responsible for its function. Transcription factors (TFs) regulate gene expression through inhibition or activation and microRNAs (miRs) do this through inhibition. There is high expression of macrophages and mast cells within the SN connective tissue. ‘Novel’/unexplored TFs and miRs in the regulation of ion channels and immune cells in the SN are not well understood. Using RNAseq and bioinformatics, the expression profile and predicted interaction of key TFs and cell markers with key miRs in the adult human SN vs. right atrial tissue (RA) were determined.

Principal results

68 and 60 TFs significantly more or less expressed in the SN vs. RA respectively. Among those more expressed were ISL1 and TBX3 (involved in embryonic development of the SN) and ‘novel’ RUNX1-2, CEBPA, GLI1-2 and SOX2. These TFs were predicted to regulate HCN4 expression in the SN. Markers for different cells: fibroblasts (COL1A1), fat (FABP4), macrophages (CSF1R and CD209), natural killer (GZMA) and mast (TPSAB1) were significantly more expressed in the SN vs. RA. Interestingly, RUNX1-3, CEBPA and GLI1 also regulate expression of these cells. MiR-486-3p inhibits HCN4 and markers involved in immune response.

Major conclusions

In conclusion, RUNX1-2, CSF1R, TPSAB1, COL1A1 and HCN4 are highly expressed in the SN but not miR-486-3p. Their complex interactions can be used to treat SN dysfunction such as bradycardia. Interestingly, another research group recently reported miR-486-3p is upregulated in blood samples from severe COVID-19 patients who suffer from bradycardia.

中文翻译：

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进一步了解人类窦房结的分子复杂性——“新型”转录因子和 microRNA 的作用

 研究目的

窦房结 (SN) 是心脏的主要起搏器。 SN 中的关键离子通道（主要是有趣的通道，HCN4）和 Ca ²⁺处理蛋白负责其功能。转录因子 (TF) 通过抑制或激活来调节基因表达，而 microRNA (miR) 通过抑制来调节基因表达。 SN 结缔组织内巨噬细胞和肥大细胞高表达。 SN 中离子通道和免疫细胞调节中的“新颖”/未开发的 TF 和 miR 尚不清楚。使用 RNAseq 和生物信息学，确定了成人 SN 与右心房组织 (RA) 中关键 TF 和细胞标记物与关键 miR 的表达谱和预测相互作用。

 主要成果

68 和 60 个 TF 在 SN 与 RA 中分别显着或多或少表达。其中表达较多的是 ISL1 和 TBX3（参与 SN 的胚胎发育）以及“新的”RUNX1-2、CEBPA、GLI1-2 和 SOX2。预计这些 TF 会调节 SN 中的 HCN4 表达。不同细胞的标记物：成纤维细胞 (COL1A1)、脂肪 (FABP4)、巨噬细胞 (CSF1R 和 CD209)、自然杀伤细胞 (GZMA) 和肥大细胞 (TPSAB1) 在 SN 中的表达量显着高于 RA。有趣的是，RUNX1-3、CEBPA 和 GLI1 也调节这些细胞的表达。 MiR-486-3p 抑制 HCN4 和参与免疫反应的标记物。

 主要结论

总之，RUNX1-2、CSF1R、TPSAB1、COL1A1 和 HCN4 在 SN 中高表达，但 miR-486-3p 中不高表达。它们复杂的相互作用可用于治疗 SN 功能障碍，例如心动过缓。有趣的是，另一个研究小组最近报告称，患有心动过缓的重症 COVID-19 患者的血液样本中 miR-486-3p 上调。